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Histone deacetylase inhibitor induced modulation of anti-estrogen therapy
Cancer Letters 280 (2009) 184–191
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Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review
Histone deacetylase inhibitor induced modulation of anti-estrogen therapy Scott Thomas, Pamela N. Munster * Division of Hematology and Oncology, University of California, San Francisco San Francisco, CA 94143, United States
a r t i c l e
i n f o
Article history: Received 29 October 2008 Received in revised form 17 November 2008 Accepted 10 December 2008
Keywords: Histone deacetylases HDAC HDAC inhibitors Breast cancer Estrogen receptor Progesterone receptor Anti-estrogen therapy
a b s t r a c t Histone deacetylase (HDAC) inhibitors are a novel class of anti-tumor agents with a potential role in the treatment of breast cancer. In ER-positive cells, treatment with selective and non-selective HDAC inhibitors has been associated with a transcriptional down-regulation (and possibly protein modification via the HSP90 chaperone function) of ER and its response genes. In ER-negative cell lines, HDAC inhibitors have been shown to re-establish ER expression. In addition, HDAC inhibitors have been reported to modulate the progesterone receptor. Despite the opposing effects in ER-positive and ER-negative breast cancer cells, the addition of an HDAC inhibitor potentiated and restored the efficacy of anti-estrogen therapy in preclinical models. This has led to the initiation of several clinical trials combining HDAC inhibitors with anti-estrogen therapy. In this review, we will summarize the relationship between estrogen signaling and HDACs, examine how HDAC inhibitors impact this relationship and synergize with anti-estrogens to inhibit tumor growth, and discuss the clinical possibilities and potential of this new approach. Ó 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. The role of estrogen receptors (ER) in breast cancer
Despite many recent advances, breast cancer continues to be one of the most serious diseases to afflict women. World-wide, 548,000 women are estimated to die annually from breast cancer (1: http://www.who.int/mediacentre/ factsheets/fs297/en/index.html). The therapeutic approach for women with breast cancer includes a combination of chemotherapy, targeted and hormonal therapy. The latter is limited to patients with tumors over-expressing steroid hormone receptors such as estrogen receptors (ER) and progesterone receptors (PR). In the Western world, about 65% of patients present with tumors that express either one receptor (ER or PR), or both, with a higher percentage of older patients presenting with ER-positive tumors [1,2]. Emerging data suggest that tumors over-expressing hormone receptors may be more resistant to chemotherapy [3], hence pointing to the need for effective hormonal therapy with limited toxicity.
Estrogen-mediated signaling plays an essential role in the normal development and physiology of the breast as well as tumorigenesis. Estrogen influences cell behavior through its interaction with estrogen receptors (ERs; ERa and ERb), which are members of the nuclear hormone receptor superfamily [4,5]. Binding of estrogen to ER induces a conformational change in the ER that favors its dimerization and recruitment to promoter elements either directly through its DNA binding domain or indirectly through other transcription factors [6]. ER complexes recruit co-regulators (e.g. co-activators and co-repressors) and transcription factors to promote or inhibit gene transcription [4]. The preferential induction of co-repressors or co-activators is tissue-specific and differentially regulated by various therapeutic anti-estrogens. Additionally, ER has been shown to have estrogen independent transcriptional activity, which is mediated by growth factor signaling pathways via ER phosphorylation [7,8]. Estrogen-mediated signaling mediates the transcription of a host of genes affecting a number of cellular pathways and processes, including the transcriptional regulation of
* Corresponding author. Tel.: +1 415 353 7287. E-mail address: [email protected] (P.N. Munster). 0304-3835/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2008.12.026
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progesterone receptor (PR), as well as ERa through an auto-regulatory mechanism [9–11]. In many breast cancers, estrogen-mediated signaling plays a central role in the modulation of pro-growth and pro-survival signaling pathways and can directly drive tumorigenesis by inducing the expression of genes such as cyclin D1, transforming growth factor alpha, and insulin-like growth factor-1 [12–17]. The level of hormone receptor expression in breast cancer has prognostic and predictive implications [18–21]. The therapeutic modulation of estrogen signaling pathways is one of the first recognized targeted therapies. The most commonly used modalities include compounds that modulate or down-regulate estrogen receptors, including the SERM (selective estrogen receptor modulator), tamoxifen (NolvadexÒ) or the SERD (selective estrogen receptor down-regulator), fulvestrant (FaslodexÒ). Upon the menopausal cessation of estrogen production by the ovary, estradiol is mainly synthesized in peripheral tissues through the aromatization of androgens to estrogens. The inhibition of tissue aromatization using any of the three approved aromatase inhibitors (anastrozole (ArimidexÒ), letrozole (FemaraÒ), exemestane, AromasinÒ) is considered the preferred treatment for post-menopausal patients [22– 24]. A third modality includes the surgical or chemical suppression of ovarian function in premenopausal women, however this approach is more commonly used in combination with one of the pharmacological interventions [25,26]. The effectiveness of hormone therapy is directly linked to the expression and functionality of both ER and PR. Retrospective studies and clinical trails have demonstrated that tumors expressing both ER and PR respond significantly better to hormone therapy than those with low receptor expression [18,27–30]. In a recent study, ER and PR expression was evaluated in tumors from more than 50,000 breast cancer patients. The investigators found that the majority of patients with hormone receptor positive tumors express both ER and PR (57%), while smaller groups present with ER+/PR tumors (27%), ER/PR+ tumors (3%), and ER/PR tumors (13%) [31]. Several clinical studies have suggested a worse outcome in patients with ER+/ PR tumors; however whether this is a surrogate marker of aberrant growth [31] or due increased resistance to hormone therapy remains debatable. The expression of PR in the absence of ER expression (ER/PR+) is rare, but has been implicated with a younger age, higher-risk disease and decreased benefits from hormonal therapy [32,33]. Even among patients expressing both ER and PR, a benefit from hormonal therapy is seen in less than 50% of the cases, and the response to therapy is often not durable.
3. HDACs and their inhibitors in breast cancer Currently, much emphasis is being placed on developing novel strategies to reverse hormone therapy resistance. One such approach involves the use of histone deacetylase (HDAC) inhibitors either alone or in combination with existing therapies. HDAC inhibitors have emerged as a promising new class of anti-cancer agents with the first
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in its class (vorinostat, ZolinzaÒ) recently approved for the treatment of cutaneous T-cell lymphoma. HDAC inhibitors have been shown to have activity against other hematological malignancies, however their activity against solid tumor malignancies remains limited (reviewed by Issa et al. in this issue). For solid tumor malignancies, more emphasis has therefore been placed on defining the optimal tumor type likely to benefit from HDAC inhibitors and to study mechanistically rational combinations. There are several ongoing trials to test HDAC inhibitors in combination with either biologic therapies, cytotoxic therapies or hormonal therapies (www.clinicaltrials.gov). At least four structurally different classes of HDAC inhibitors are currently being evaluated, many of which are further subdivided by their potency against select HDAC enzymes. To date, there is still only limited data on the clinical relevance of the structural differences of the select HDAC inhibitors or the importance of tissue-specific expression of individual HDAC enzymes. Therefore, the anticipated tissue- and drug-selectivity may account for the discordant biological and molecular behavior observed in reports involving HDAC inhibitors. 4. Differential HDAC enzyme expression in breast cancer Several investigators have reported a link between HDAC1 and HDAC3 expression and specific characteristics of breast tumors. RT-PCR analysis of HDAC1 mRNA levels and immunohistochemical analysis of HDAC1 and HDAC3 protein expression demonstrated they were statistically associated with smaller, estrogen- and progesterone-positive tumors, while HDAC1 mRNA, but not HDAC1 protein expression was linked to node-negative tumors [34,35]. Furthermore, increased HDAC1 mRNA and protein expression were linked to better outcome, while HDAC3 expression did not appear to impact overall or disease-free survival [34,35]. However, the reports were equivocal as to whether HDAC1 mRNA was an independent prognostic indicator or linked to other features [34]. A retrospective analysis of banked tumor tissues suggested that increased expression of HDAC6 was associated with improved disease-free and overall survival in patients with hormonesensitive breast tumors treated with tamoxifen [36].
5. HDAC-associated modulation of estrogen receptor HDAC family members are involved in the acetylation state of histone and non-histone targets and may play an important role in the transcriptional regulation of many signaling pathways including estrogen- and progesterone-mediated signaling. At several points in the estrogen-mediated signal transduction pathway, acetylation has been found to be a key mediator, regulating both the transcription and turnover of ER [37]. The transcriptional regulation of ERa is complex, with at least seven promoters producing a number of different transcripts, at various levels, differing by cell and tissue type [38]. Several studies suggest that the aberrant activity of corepressor complexes containing DNA methyltransfer-
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ases (DNMT) and HDACs contribute to the loss of ER expression in ER-negative tumors. Lapidus et al. found that in roughly 25% of ER-negative tumors the ER promoter was methylated, while in the ER-positive tumors ER promoter methylation was not observed [39]. In MDA-MB-231 cells, the transcriptional co-repressors, DNMT1, 3a and b, methyl binding proteins (MBPs; MeCP2, MBD1, and MBD2), and HDAC1, were found to associate with the silenced ERa promoter [40]. DNMT1 has been shown to form complexes with HDAC1 and HDAC2 [41,42]. Treatment of MDA-MB231 cells with both the HDAC inhibitor TSA and the DNMT inhibitor 5-aza-20 -deoxycytidine released HDAC1, DNMT1 and the MBPs from the ERa promoter. In these cells, histones exhibited increased acetylation and H3-K4 methylation and diminished H3-K9 methylation, hallmarks of transcriptionally active chromatin, and reactivation of ERa expression [40,43]. Furthermore, treatment of MDAMB-435 cells with 5-aza-20 -deoxycytidine and TSA has been shown to re-establish their response to hormone therapy [44]. Consistent with these findings, Kawai et al. showed that overexpression of HDAC1 in ERa positive MCF-7 cells repressed ERa expression, which was experimentally reactivated by the HDAC inhibitor, TSA [45]. However, treatment of MDA-MB-231 cells with an HDAC inhibitor alone, such as vorinostat, TSA or VPA, has been shown to elicit only a modest or minimal increase in ERa mRNA expression with an accompanied increase in histone acetylation by other investigators at therapeutic concentrations of the examined HDAC inhibitor [40,46,47]. However, Jang et al. found that treatment of MDA-MB-231 cells with TSA stimulated transcription and expression of ERb but not ERa, with subsequent transactivation of target genes. Additionally, they found that ERb nuclear translocation was increased when cells were treated with TSA and exhibited a synergistic response to tamoxifen [48]. Thus, acetylation and methylation appear to cooperatively regulate the chromatin surrounding the ERa gene and in turn its transcription, and that the activation of ERa expression in ER-negative cells, at least in part, requires the reversal of epigenetic silencing. In contrast to ER-negative breast cancer cells, the treatment of ER-positive cells with selective and non-selective HDAC inhibitors have been associated with a transcriptional down-regulation of ERa and its response genes [46,47]. Treatment of MCF-7 cells with the HDAC inhibitor vorinostat resulted in a reduction of ERa mRNA followed by a reduction in ERa protein. Inhibition of the proteasome abrogated the affect of vorinostat on ERa protein degradation but not the reduction in mRNA [49]. Alao et al. reported a similar reduction in ERa mRNA in MCF-7 cells with the treatment of the HDAC inhibitor, TSA. Concomitant treatment with the protein translation inhibitor cyclohexamide and TSA did not affect the observed repression of ERa transcription, suggesting a direct role for HDAC activity in the maintenance of ERa transcription and likely a distinct mechanism for the regulation of its protein levels [50]. However, in a contradictory report by Reid et al., the authors found that treating MCF-7 cells with either the HDAC inhibitor VPA or TSA resulted in a rapid reduction in ERa mRNA, but the addition of cyclohexamide stabilized ERa mRNA. Therefore, the authors proposed that
ERa mRNA reduction observed with HDAC inhibitor treatment was not direct, but rather through the expression or repression of one or more proteins that modulate ERa transcription [38]. One explanation for this observed difference might be the choice of HDAC inhibitor employed, vorinostat versus TSA and VPA. Although both TSA and vorinostat are hydroxamic acids, Khan et al. have shown that the effect on the transcriptional regulation of target genes has a considerable range not only between HDAC inhibitors from different classes but even within the same class of drugs, [51] which may account for the disparate findings. Whether the affect of HDAC activity on ERa transcription is direct, indirect or both, the differential affect in ER-positive versus -negative cells remains intriguing and demonstrates the need for more mechanistic studies in this field to define the optimal clinical setting for further testing of these agents for women with breast cancer. The understanding of ER modulation by HDAC inhibitors entails further complexity as with many nuclear receptors, the HSP90 chaperone complex plays a key role in estrogen signaling. The Hsp90 chaperone complex binds to and maintains ERa in a ligand-binding conformation [52,53]. Inhibition of Hsp90 chaperone activity results in ubiquitin-mediated degradation of ERa by the proteasome [54]. The chaperone function of Hsp90 has been shown to depend on HDAC activity, with HDAC6 being directly implicated [55–57]. HDAC6-specific inhibition results in hyper-acetylation of Hsp90, diminished association with ERa, and resultant ERa ubiquitination and depletion. Consistent with the turnover of ERa, estrogen-mediated transcriptional activity is reduced [58]. Therefore, acetylation represents an important mechanism through which the cell can modulate estrogen-mediated signaling by limiting available ERa. As HDAC6 appears to be the key deacetylase regulating Hsp90, perturbing this regulation should be limited to the hydroxamic or pan-HDAC inhibitors. Indeed, treatment of breast cancer cells with Hsp90 inhibitors or vorinostat leads to functional and morphological mammary cell differentiation (Fig. 1) [59].
6. HDAC-associated modulation of progesterone receptor The clinical thrust of hormonal therapy is centered on targeting ER. While the function and expression of ER is a predictive factor of anti-estrogen therapy, the role of PR as a predictive factor has remained less clear. While earlier trials with aromatase inhibitors suggested a role for PR as a predictive factor [60], more recent studies have not confirmed these findings [18]. Nonetheless, there is emerging data suggesting an independent role of PR as a prognostic factor. Several investigators have shown an association of PR with tumor proliferation as well as tumor invasion in preclinical models [61–65]. PR is expressed in two forms: PRA and PRB [9]. These isoforms are transcribed from two distinct sites but within the same gene [66]. The control of growth, transformation and invasion is not only regulated by the degree of expression of PR, but also by the balance between the two isoforms. In normal breast tissue, PRA and PRB are typically found in equimolar levels,
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Fig. 1. The HDAC inhibitor vorinostat induces breast cancer cell differentiation. A common marker of breast cell differentiation is the production of milk droplets, which consist of lipids and proteins. Confocal microscopy (63) of MCF-7 cells cultured in the presence of vorinostat for 48 h (B) showed induction of the milk fat proteins MFG (milk fat globulin, green) and MFGM (milk fat globule membrane, red), compared to MCF-7 cells cultured without vorinostat (A). Nuclear DNA was stained with DAPI (blue) (For interpretation of the references in color in this figure legend, the reader is referred to the web version of this article.).
whereas transformation to a malignant phenotype has been associated with a change in the ratio between the two isoforms with predominant expression of PRA [67]. The PRA isoform has been shown to directly repress PRB function. In addition to its function in cell signaling, preclinical studies suggest that dysfunctional PR regulation may result in increased invasiveness [68,69]. The clinical assessment of PR has been proved to be more difficult than for ER. Hence, the difficulties in defining the relevance of PR for clinical outcomes may be at least in part be due to the less robust reproducibility of the tissue assessment for PR. While the expression of PR may not predict the response to anti-therapy, PR may play a role in the HDAC inhibitor induced sensitization of breast cancer to hormonal therapy. Several investigators have reported a modulation of PR by HDAC inhibitors. Yang et al. noted an increase in the expression of PR, that paralleled the HDAC inhibitor mediated modulation of ER in ER-negative cells [43]. Similar findings were recently reported by Travaglini et al., where they showed that in MCF-7 cells, VPA reduced the expression of PR via modulation of the estrogen response element after reduction of ER, whereas in the ER- and PR-negative cell line, MDA-231, PR was reactivated [47]. In contrast, Reid et al. suggest that the modulation of ER and its response elements may be affected via direct gene modulation as well as indirect modulation through the effects on co-repressors and co-activators [38]. Fiskus et al. reported an indirect effect on PRB through hyperactylation of HSP90 via HDAC6 inhibition by the hydroxamic type HDAC inhibitors. Studies by Bicaku et al. suggested that both class-specific and class-selective HDAC inhibitors decreased the expression of ER and PR in ER-positive cells, however the group did not see a reactivation of ER or PR at clinically feasible concentrations of VPA and vorinostat. As VPA does
not inhibit HDAC6, these effects may be independent of HSP90-mediated post-transcriptional modification. Furthermore, the select depletion of HDAC6 did not result in the modulation of PR. Selective depletion of HDAC2, but not HDAC1 or HDAC6, by siRNA resulted in the depletion of both ER and PR mRNA and protein [46]. Taken together these reports suggest that both ER and PR may be modulated at different levels and the effects are dependent on the baseline expression of the nuclear receptors. 7. HDAC inhibitors and hormonal therapy Given the interaction of HDACs with the ER at various levels, it is not surprising that HDAC inhibitors have been reported to affect breast tumor cell growth, potentiate anti-estrogen therapy and/or lead to a reversal of tamoxifen resistance (Fig. 2). Hirokawa et al. showed that treatment of tamoxifen sensitive and insensitive MCF-7 cells with the HDAC inhibitor FK228 inhibited tumor cell growth in vitro and in vivo [70]. Additionally, others have shown that the growth arrest and differentiation witnessed with HDAC inhibitor treatment is reversible upon drug removal, and when administered at clinically feasible concentrations very little apoptosis is induced [59]. Hence, HDAC inhibitors may be more efficacious in combination with hormonal therapy. Indeed, several laboratories have reported that HDAC inhibitors potentiate the effects of tamoxifen in ER-positive cells and reversed hormone resistance in ER-negative or tamoxifen-resistant cells [36,37,44,48,58,70–75]. Initial investigations suggest that this interaction is not limited to tamoxifen, but may also be translated to aromatase inhibitors [71]. Several studies have explored the mechanism underlying the additive or synergistic interactions between HDAC inhibitors and hormonal therapy. As described above, the HDAC inhibitors extensively modulate both steroid recep-
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Fig. 2. HDAC inhibitors and anti-estrogen therapy interfere with estrogen signaling at various points.
tors, ER and PR. In addition, it appears that several HDAC enzymes function independently to carry out different roles. When bound to tamoxifen, ER has been shown to associate at target promoters with the corepressor complexes, NCoR and NuRD, which contain HDAC2 and HDAC3. These promoters were transcriptionally repressed. On the other hand, when complexed with estradiol, HDAC2 and HDAC3 were not recruited to these promoters [72]. To ascertain the combined affect of tamoxifen and HDAC inhibitors on ERa targeted transcription, Margueron et al. utilized a genome integrated reporter containing an estrogen response element. When low concentrations of TSA or vorinostat were given together with tamoxifen, tamoxifen acted as a transcriptional ER antagonist. Interestingly, at higher concentrations of TSA or vorinostat, the tamoxifen
switched to act as an ER agonist. The authors suggest that this may be due to the inhibition of (an) additional HDAC(s) at higher concentrations, exemplifying the importance of HDAC inhibitor dosage [37]. As described above, treating ER-negative cells with the combination of an HDAC and DNMT (AZA) inhibitor restores expression of ERa mRNA and inhibits tumor growth. In addition, this treatment restores sensitivity to tamoxifen in in vitro models [44]. In another study, Jang et al. provide evidence that ERb plays an important role in the response to tamoxifen. When MDA-MB-231 and Hs578T ER-negative breast cancer cells were treated with TSA, an increase in ERb but not ERa, expression and nuclear import was observed. This was accompanied with increased responsiveness to tamoxifen. Subsequent depletion of ERb by siRNA abrogated
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tamoxifen response in these cells [48]. Furthermore, others have shown that the sensitization of ER-positive but not ER-negative cells to tamoxifen can be triggered through inhibition of HDAC2 [46]. Collectively these studies indicate a highly complex and possibly very distinct interaction between estradiol (and its mediation by aromatase inhibitors) and tamoxifen with HDAC inhibitors. The underlying mechanism to potentiate hormonal therapy or to reverse hormone therapy resistance may vary fundamentally with different classes of HDAC inhibitors, drug concentrations of the inhibitors and the duration of exposure.
8. Recent clinical advances involving HDAC inhibitors in breast cancer Several HDAC inhibitors have been studied in early clinical trials, including breast cancer. As single agents the HDAC inhibitors have shown limited activity in patients with solid tumor malignancies. A Phase II clinical trial evaluating vorinostat as a single agent showed disease stabilization, but no objective responses were seen and the trial was stopped early [76]. Based on preclinical studies from our laboratory and other investigators, we initiated a clinical trial that is currently enrolling patients, combining vorinostat and tamoxifen in women with ER-positive metastatic breast cancer whose tumor progressed during treatment with aromatase inhibitors. Patients may have been treated with tamoxifen during their adjuvant treatment and may have been further exposed to as many as three chemotherapy regimens in the metastatic setting. Enrollment criteria excluded patients with tamoxifen or fulvestrant treatment for metastatic disease, a history of brain metastases or thromboembolic events. A preliminary report of the trial was presented at the American Society of Clinical Oncology. In the first 25 patients, five of 24 evaluable patients (21%) had an objective response by RECIST criteria and 8/24 (33%) had disease stabilization. Four of the five patients received two prior aromatase inhibitors and two received tamoxifen in the adjuvant setting. Additionally, two of the five patients had prior chemotherapy for metastatic disease. Of the patients with stable disease all but one had prior tamoxifen and chemotherapy. Of the 13 patients exhibiting a benefit from the combination treatment, eight patients expressed both ER and PR, while five patients expressed ER but not PR ([73] and www.asco.org/ASCO/ Abstracts+&+Virtual+Meeting/). While preliminary, these results are encouraging as the expected response rate at this stage of disease for tamoxifen alone is less than 10% and the trial examining vorinostat alone elicited no responses. This trial will continue to enroll patients, with completion anticipated by the end of 2008 (www.clinicaltrials.gov). Several additional trials involving the combination of an HDAC inhibitor, including vorinostat (SAHA), panobinostat (LBH589), valproic acid (VPA) or entinostat (SNDX-275) and either tamoxifen, fulvestrant or an aromatase inhibitor, are underway or in planning.
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9. Future directions There is an evolving body of literature to suggest a benefit in adding an HDAC inhibitor to hormonal therapy either upfront to potentiate anti-estrogen therapy or to reverse hormone therapy resistance. However, the presented reports suggest that the HDAC inhibitor induced modulation of ER and its down-stream targets is complex, and likely depends on the baseline expression of ER, PR or both as well as other signaling factors. The effects may further vary with the HDAC inhibitor type and its drug concentrations. The underlying mechanism of the observed synergistic interaction may be different for a specific cell type and whether the combination partner is an anti-estrogen or an aromatase inhibitor. Greater mechanistic insight will likely allow for therapeutic approaches that better tailor to specific tumor cell biology. References [1] L. Livi, F. Paiar, C. Saieva, G. Simontacchi, J. Nori, L. Sanchez, R. Santini, M. Mangoni, S. Fondelli, V. Distante, S. Bianchi, G. Biti, Breast cancer in the elderly: treatment of 1500 patients, Breast J. 12 (2006) 353–359. [2] Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials, Lancet 365 (2005) 1687–1717. [3] S.H. Giordano, Z. Duan, Y.F. Kuo, G.N. Hortobagyi, J.S. Goodwin, Use and outcomes of adjuvant chemotherapy in older women with breast cancer, J. Clin. Oncol. 24 (2006) 2750–2756. [4] J. Matthews, J.A. Gustafsson, Estrogen signaling: a subtle balance between ER alpha and ER beta, Mol. Interv. 3 (2003) 281–292. [5] G.G. Kuiper, E. Enmark, M. Pelto-Huikko, S. Nilsson, J.A. Gustafsson, Cloning of a novel receptor expressed in rat prostate and ovary, Proc. Natl. Acad. Sci. USA 93 (1996) 5925–5930. [6] S.E. Fawell, J.A. Lees, R. White, M.G. Parker, Characterization and colocalization of steroid binding and dimerization activities in the mouse estrogen receptor, Cell 60 (1990) 953–962. [7] G. Bunone, P.A. Briand, R.J. Miksicek, D. Picard, Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation, EMBO J. 15 (1996) 2174–2183. [8] A. Tremblay, G.B. Tremblay, F. Labrie, V. Giguere, Ligandindependent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1, Mol. Cell. 3 (1999) 513–519. [9] P. Kastner, A. Krust, B. Turcotte, U. Stropp, L. Tora, H. Gronemeyer, P. Chambon, Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B, Embo J. 9 (1990) 1603–1614. [10] L. Chan, B.W. O’Malley, Mechanism of action of the sex steroid hormones (second of three parts), N. Engl. J. Med. 294 (1976) 1372– 1381. [11] J.R. Schultz, L.N. Petz, A.M. Nardulli, Estrogen receptor alpha and Sp1 regulate progesterone receptor gene expression, Mol. Cell. Endocrinol. 201 (2003) 165–175. [12] D. El-Ashry, S.A. Chrysogelos, M.E. Lippman, F.G. Kern, Estrogen induction of TGF-alpha is mediated by an estrogen response element composed of two imperfect palindromes, J. Steroid Biochem. Mol. Biol. 59 (1996) 261–269. [13] F.S. Kenny, R. Hui, E.A. Musgrove, J.M. Gee, R.W. Blamey, R.I. Nicholson, R.L. Sutherland, J.F. Robertson, Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptorpositive breast cancer, Clin. Cancer Res. 5 (1999) 2069–2076. [14] E. Castro-Rivera, I. Samudio, S. Safe, Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements, J. Biol. Chem. 276 (2001) 30853–30861. [15] V. Dubois, D. Couissi, E. Schonne, Y.J. Schneider, C. Remacle, A. Trouet, Estrogen and insulin modulation of intracellular insulin-like growth factor binding proteins in human breast cancer cells: possible involvement in lysosomal hydrolases oversecretion, Biochem. Biophys. Res. Commun. 192 (1993) 295–301. [16] J.A. Figueroa, J.G. Jackson, W.L. McGuire, R.F. Krywicki, D. Yee, Expression of insulin-like growth factor binding proteins in human
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Contents lists available at ScienceDirect
Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review
Histone deacetylase inhibitor induced modulation of anti-estrogen therapy Scott Thomas, Pamela N. Munster * Division of Hematology and Oncology, University of California, San Francisco San Francisco, CA 94143, United States
a r t i c l e
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Article history: Received 29 October 2008 Received in revised form 17 November 2008 Accepted 10 December 2008
Keywords: Histone deacetylases HDAC HDAC inhibitors Breast cancer Estrogen receptor Progesterone receptor Anti-estrogen therapy
a b s t r a c t Histone deacetylase (HDAC) inhibitors are a novel class of anti-tumor agents with a potential role in the treatment of breast cancer. In ER-positive cells, treatment with selective and non-selective HDAC inhibitors has been associated with a transcriptional down-regulation (and possibly protein modification via the HSP90 chaperone function) of ER and its response genes. In ER-negative cell lines, HDAC inhibitors have been shown to re-establish ER expression. In addition, HDAC inhibitors have been reported to modulate the progesterone receptor. Despite the opposing effects in ER-positive and ER-negative breast cancer cells, the addition of an HDAC inhibitor potentiated and restored the efficacy of anti-estrogen therapy in preclinical models. This has led to the initiation of several clinical trials combining HDAC inhibitors with anti-estrogen therapy. In this review, we will summarize the relationship between estrogen signaling and HDACs, examine how HDAC inhibitors impact this relationship and synergize with anti-estrogens to inhibit tumor growth, and discuss the clinical possibilities and potential of this new approach. Ó 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. The role of estrogen receptors (ER) in breast cancer
Despite many recent advances, breast cancer continues to be one of the most serious diseases to afflict women. World-wide, 548,000 women are estimated to die annually from breast cancer (1: http://www.who.int/mediacentre/ factsheets/fs297/en/index.html). The therapeutic approach for women with breast cancer includes a combination of chemotherapy, targeted and hormonal therapy. The latter is limited to patients with tumors over-expressing steroid hormone receptors such as estrogen receptors (ER) and progesterone receptors (PR). In the Western world, about 65% of patients present with tumors that express either one receptor (ER or PR), or both, with a higher percentage of older patients presenting with ER-positive tumors [1,2]. Emerging data suggest that tumors over-expressing hormone receptors may be more resistant to chemotherapy [3], hence pointing to the need for effective hormonal therapy with limited toxicity.
Estrogen-mediated signaling plays an essential role in the normal development and physiology of the breast as well as tumorigenesis. Estrogen influences cell behavior through its interaction with estrogen receptors (ERs; ERa and ERb), which are members of the nuclear hormone receptor superfamily [4,5]. Binding of estrogen to ER induces a conformational change in the ER that favors its dimerization and recruitment to promoter elements either directly through its DNA binding domain or indirectly through other transcription factors [6]. ER complexes recruit co-regulators (e.g. co-activators and co-repressors) and transcription factors to promote or inhibit gene transcription [4]. The preferential induction of co-repressors or co-activators is tissue-specific and differentially regulated by various therapeutic anti-estrogens. Additionally, ER has been shown to have estrogen independent transcriptional activity, which is mediated by growth factor signaling pathways via ER phosphorylation [7,8]. Estrogen-mediated signaling mediates the transcription of a host of genes affecting a number of cellular pathways and processes, including the transcriptional regulation of
* Corresponding author. Tel.: +1 415 353 7287. E-mail address: [email protected] (P.N. Munster). 0304-3835/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2008.12.026
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progesterone receptor (PR), as well as ERa through an auto-regulatory mechanism [9–11]. In many breast cancers, estrogen-mediated signaling plays a central role in the modulation of pro-growth and pro-survival signaling pathways and can directly drive tumorigenesis by inducing the expression of genes such as cyclin D1, transforming growth factor alpha, and insulin-like growth factor-1 [12–17]. The level of hormone receptor expression in breast cancer has prognostic and predictive implications [18–21]. The therapeutic modulation of estrogen signaling pathways is one of the first recognized targeted therapies. The most commonly used modalities include compounds that modulate or down-regulate estrogen receptors, including the SERM (selective estrogen receptor modulator), tamoxifen (NolvadexÒ) or the SERD (selective estrogen receptor down-regulator), fulvestrant (FaslodexÒ). Upon the menopausal cessation of estrogen production by the ovary, estradiol is mainly synthesized in peripheral tissues through the aromatization of androgens to estrogens. The inhibition of tissue aromatization using any of the three approved aromatase inhibitors (anastrozole (ArimidexÒ), letrozole (FemaraÒ), exemestane, AromasinÒ) is considered the preferred treatment for post-menopausal patients [22– 24]. A third modality includes the surgical or chemical suppression of ovarian function in premenopausal women, however this approach is more commonly used in combination with one of the pharmacological interventions [25,26]. The effectiveness of hormone therapy is directly linked to the expression and functionality of both ER and PR. Retrospective studies and clinical trails have demonstrated that tumors expressing both ER and PR respond significantly better to hormone therapy than those with low receptor expression [18,27–30]. In a recent study, ER and PR expression was evaluated in tumors from more than 50,000 breast cancer patients. The investigators found that the majority of patients with hormone receptor positive tumors express both ER and PR (57%), while smaller groups present with ER+/PR tumors (27%), ER/PR+ tumors (3%), and ER/PR tumors (13%) [31]. Several clinical studies have suggested a worse outcome in patients with ER+/ PR tumors; however whether this is a surrogate marker of aberrant growth [31] or due increased resistance to hormone therapy remains debatable. The expression of PR in the absence of ER expression (ER/PR+) is rare, but has been implicated with a younger age, higher-risk disease and decreased benefits from hormonal therapy [32,33]. Even among patients expressing both ER and PR, a benefit from hormonal therapy is seen in less than 50% of the cases, and the response to therapy is often not durable.
3. HDACs and their inhibitors in breast cancer Currently, much emphasis is being placed on developing novel strategies to reverse hormone therapy resistance. One such approach involves the use of histone deacetylase (HDAC) inhibitors either alone or in combination with existing therapies. HDAC inhibitors have emerged as a promising new class of anti-cancer agents with the first
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in its class (vorinostat, ZolinzaÒ) recently approved for the treatment of cutaneous T-cell lymphoma. HDAC inhibitors have been shown to have activity against other hematological malignancies, however their activity against solid tumor malignancies remains limited (reviewed by Issa et al. in this issue). For solid tumor malignancies, more emphasis has therefore been placed on defining the optimal tumor type likely to benefit from HDAC inhibitors and to study mechanistically rational combinations. There are several ongoing trials to test HDAC inhibitors in combination with either biologic therapies, cytotoxic therapies or hormonal therapies (www.clinicaltrials.gov). At least four structurally different classes of HDAC inhibitors are currently being evaluated, many of which are further subdivided by their potency against select HDAC enzymes. To date, there is still only limited data on the clinical relevance of the structural differences of the select HDAC inhibitors or the importance of tissue-specific expression of individual HDAC enzymes. Therefore, the anticipated tissue- and drug-selectivity may account for the discordant biological and molecular behavior observed in reports involving HDAC inhibitors. 4. Differential HDAC enzyme expression in breast cancer Several investigators have reported a link between HDAC1 and HDAC3 expression and specific characteristics of breast tumors. RT-PCR analysis of HDAC1 mRNA levels and immunohistochemical analysis of HDAC1 and HDAC3 protein expression demonstrated they were statistically associated with smaller, estrogen- and progesterone-positive tumors, while HDAC1 mRNA, but not HDAC1 protein expression was linked to node-negative tumors [34,35]. Furthermore, increased HDAC1 mRNA and protein expression were linked to better outcome, while HDAC3 expression did not appear to impact overall or disease-free survival [34,35]. However, the reports were equivocal as to whether HDAC1 mRNA was an independent prognostic indicator or linked to other features [34]. A retrospective analysis of banked tumor tissues suggested that increased expression of HDAC6 was associated with improved disease-free and overall survival in patients with hormonesensitive breast tumors treated with tamoxifen [36].
5. HDAC-associated modulation of estrogen receptor HDAC family members are involved in the acetylation state of histone and non-histone targets and may play an important role in the transcriptional regulation of many signaling pathways including estrogen- and progesterone-mediated signaling. At several points in the estrogen-mediated signal transduction pathway, acetylation has been found to be a key mediator, regulating both the transcription and turnover of ER [37]. The transcriptional regulation of ERa is complex, with at least seven promoters producing a number of different transcripts, at various levels, differing by cell and tissue type [38]. Several studies suggest that the aberrant activity of corepressor complexes containing DNA methyltransfer-
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ases (DNMT) and HDACs contribute to the loss of ER expression in ER-negative tumors. Lapidus et al. found that in roughly 25% of ER-negative tumors the ER promoter was methylated, while in the ER-positive tumors ER promoter methylation was not observed [39]. In MDA-MB-231 cells, the transcriptional co-repressors, DNMT1, 3a and b, methyl binding proteins (MBPs; MeCP2, MBD1, and MBD2), and HDAC1, were found to associate with the silenced ERa promoter [40]. DNMT1 has been shown to form complexes with HDAC1 and HDAC2 [41,42]. Treatment of MDA-MB231 cells with both the HDAC inhibitor TSA and the DNMT inhibitor 5-aza-20 -deoxycytidine released HDAC1, DNMT1 and the MBPs from the ERa promoter. In these cells, histones exhibited increased acetylation and H3-K4 methylation and diminished H3-K9 methylation, hallmarks of transcriptionally active chromatin, and reactivation of ERa expression [40,43]. Furthermore, treatment of MDAMB-435 cells with 5-aza-20 -deoxycytidine and TSA has been shown to re-establish their response to hormone therapy [44]. Consistent with these findings, Kawai et al. showed that overexpression of HDAC1 in ERa positive MCF-7 cells repressed ERa expression, which was experimentally reactivated by the HDAC inhibitor, TSA [45]. However, treatment of MDA-MB-231 cells with an HDAC inhibitor alone, such as vorinostat, TSA or VPA, has been shown to elicit only a modest or minimal increase in ERa mRNA expression with an accompanied increase in histone acetylation by other investigators at therapeutic concentrations of the examined HDAC inhibitor [40,46,47]. However, Jang et al. found that treatment of MDA-MB-231 cells with TSA stimulated transcription and expression of ERb but not ERa, with subsequent transactivation of target genes. Additionally, they found that ERb nuclear translocation was increased when cells were treated with TSA and exhibited a synergistic response to tamoxifen [48]. Thus, acetylation and methylation appear to cooperatively regulate the chromatin surrounding the ERa gene and in turn its transcription, and that the activation of ERa expression in ER-negative cells, at least in part, requires the reversal of epigenetic silencing. In contrast to ER-negative breast cancer cells, the treatment of ER-positive cells with selective and non-selective HDAC inhibitors have been associated with a transcriptional down-regulation of ERa and its response genes [46,47]. Treatment of MCF-7 cells with the HDAC inhibitor vorinostat resulted in a reduction of ERa mRNA followed by a reduction in ERa protein. Inhibition of the proteasome abrogated the affect of vorinostat on ERa protein degradation but not the reduction in mRNA [49]. Alao et al. reported a similar reduction in ERa mRNA in MCF-7 cells with the treatment of the HDAC inhibitor, TSA. Concomitant treatment with the protein translation inhibitor cyclohexamide and TSA did not affect the observed repression of ERa transcription, suggesting a direct role for HDAC activity in the maintenance of ERa transcription and likely a distinct mechanism for the regulation of its protein levels [50]. However, in a contradictory report by Reid et al., the authors found that treating MCF-7 cells with either the HDAC inhibitor VPA or TSA resulted in a rapid reduction in ERa mRNA, but the addition of cyclohexamide stabilized ERa mRNA. Therefore, the authors proposed that
ERa mRNA reduction observed with HDAC inhibitor treatment was not direct, but rather through the expression or repression of one or more proteins that modulate ERa transcription [38]. One explanation for this observed difference might be the choice of HDAC inhibitor employed, vorinostat versus TSA and VPA. Although both TSA and vorinostat are hydroxamic acids, Khan et al. have shown that the effect on the transcriptional regulation of target genes has a considerable range not only between HDAC inhibitors from different classes but even within the same class of drugs, [51] which may account for the disparate findings. Whether the affect of HDAC activity on ERa transcription is direct, indirect or both, the differential affect in ER-positive versus -negative cells remains intriguing and demonstrates the need for more mechanistic studies in this field to define the optimal clinical setting for further testing of these agents for women with breast cancer. The understanding of ER modulation by HDAC inhibitors entails further complexity as with many nuclear receptors, the HSP90 chaperone complex plays a key role in estrogen signaling. The Hsp90 chaperone complex binds to and maintains ERa in a ligand-binding conformation [52,53]. Inhibition of Hsp90 chaperone activity results in ubiquitin-mediated degradation of ERa by the proteasome [54]. The chaperone function of Hsp90 has been shown to depend on HDAC activity, with HDAC6 being directly implicated [55–57]. HDAC6-specific inhibition results in hyper-acetylation of Hsp90, diminished association with ERa, and resultant ERa ubiquitination and depletion. Consistent with the turnover of ERa, estrogen-mediated transcriptional activity is reduced [58]. Therefore, acetylation represents an important mechanism through which the cell can modulate estrogen-mediated signaling by limiting available ERa. As HDAC6 appears to be the key deacetylase regulating Hsp90, perturbing this regulation should be limited to the hydroxamic or pan-HDAC inhibitors. Indeed, treatment of breast cancer cells with Hsp90 inhibitors or vorinostat leads to functional and morphological mammary cell differentiation (Fig. 1) [59].
6. HDAC-associated modulation of progesterone receptor The clinical thrust of hormonal therapy is centered on targeting ER. While the function and expression of ER is a predictive factor of anti-estrogen therapy, the role of PR as a predictive factor has remained less clear. While earlier trials with aromatase inhibitors suggested a role for PR as a predictive factor [60], more recent studies have not confirmed these findings [18]. Nonetheless, there is emerging data suggesting an independent role of PR as a prognostic factor. Several investigators have shown an association of PR with tumor proliferation as well as tumor invasion in preclinical models [61–65]. PR is expressed in two forms: PRA and PRB [9]. These isoforms are transcribed from two distinct sites but within the same gene [66]. The control of growth, transformation and invasion is not only regulated by the degree of expression of PR, but also by the balance between the two isoforms. In normal breast tissue, PRA and PRB are typically found in equimolar levels,
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Fig. 1. The HDAC inhibitor vorinostat induces breast cancer cell differentiation. A common marker of breast cell differentiation is the production of milk droplets, which consist of lipids and proteins. Confocal microscopy (63) of MCF-7 cells cultured in the presence of vorinostat for 48 h (B) showed induction of the milk fat proteins MFG (milk fat globulin, green) and MFGM (milk fat globule membrane, red), compared to MCF-7 cells cultured without vorinostat (A). Nuclear DNA was stained with DAPI (blue) (For interpretation of the references in color in this figure legend, the reader is referred to the web version of this article.).
whereas transformation to a malignant phenotype has been associated with a change in the ratio between the two isoforms with predominant expression of PRA [67]. The PRA isoform has been shown to directly repress PRB function. In addition to its function in cell signaling, preclinical studies suggest that dysfunctional PR regulation may result in increased invasiveness [68,69]. The clinical assessment of PR has been proved to be more difficult than for ER. Hence, the difficulties in defining the relevance of PR for clinical outcomes may be at least in part be due to the less robust reproducibility of the tissue assessment for PR. While the expression of PR may not predict the response to anti-therapy, PR may play a role in the HDAC inhibitor induced sensitization of breast cancer to hormonal therapy. Several investigators have reported a modulation of PR by HDAC inhibitors. Yang et al. noted an increase in the expression of PR, that paralleled the HDAC inhibitor mediated modulation of ER in ER-negative cells [43]. Similar findings were recently reported by Travaglini et al., where they showed that in MCF-7 cells, VPA reduced the expression of PR via modulation of the estrogen response element after reduction of ER, whereas in the ER- and PR-negative cell line, MDA-231, PR was reactivated [47]. In contrast, Reid et al. suggest that the modulation of ER and its response elements may be affected via direct gene modulation as well as indirect modulation through the effects on co-repressors and co-activators [38]. Fiskus et al. reported an indirect effect on PRB through hyperactylation of HSP90 via HDAC6 inhibition by the hydroxamic type HDAC inhibitors. Studies by Bicaku et al. suggested that both class-specific and class-selective HDAC inhibitors decreased the expression of ER and PR in ER-positive cells, however the group did not see a reactivation of ER or PR at clinically feasible concentrations of VPA and vorinostat. As VPA does
not inhibit HDAC6, these effects may be independent of HSP90-mediated post-transcriptional modification. Furthermore, the select depletion of HDAC6 did not result in the modulation of PR. Selective depletion of HDAC2, but not HDAC1 or HDAC6, by siRNA resulted in the depletion of both ER and PR mRNA and protein [46]. Taken together these reports suggest that both ER and PR may be modulated at different levels and the effects are dependent on the baseline expression of the nuclear receptors. 7. HDAC inhibitors and hormonal therapy Given the interaction of HDACs with the ER at various levels, it is not surprising that HDAC inhibitors have been reported to affect breast tumor cell growth, potentiate anti-estrogen therapy and/or lead to a reversal of tamoxifen resistance (Fig. 2). Hirokawa et al. showed that treatment of tamoxifen sensitive and insensitive MCF-7 cells with the HDAC inhibitor FK228 inhibited tumor cell growth in vitro and in vivo [70]. Additionally, others have shown that the growth arrest and differentiation witnessed with HDAC inhibitor treatment is reversible upon drug removal, and when administered at clinically feasible concentrations very little apoptosis is induced [59]. Hence, HDAC inhibitors may be more efficacious in combination with hormonal therapy. Indeed, several laboratories have reported that HDAC inhibitors potentiate the effects of tamoxifen in ER-positive cells and reversed hormone resistance in ER-negative or tamoxifen-resistant cells [36,37,44,48,58,70–75]. Initial investigations suggest that this interaction is not limited to tamoxifen, but may also be translated to aromatase inhibitors [71]. Several studies have explored the mechanism underlying the additive or synergistic interactions between HDAC inhibitors and hormonal therapy. As described above, the HDAC inhibitors extensively modulate both steroid recep-
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Fig. 2. HDAC inhibitors and anti-estrogen therapy interfere with estrogen signaling at various points.
tors, ER and PR. In addition, it appears that several HDAC enzymes function independently to carry out different roles. When bound to tamoxifen, ER has been shown to associate at target promoters with the corepressor complexes, NCoR and NuRD, which contain HDAC2 and HDAC3. These promoters were transcriptionally repressed. On the other hand, when complexed with estradiol, HDAC2 and HDAC3 were not recruited to these promoters [72]. To ascertain the combined affect of tamoxifen and HDAC inhibitors on ERa targeted transcription, Margueron et al. utilized a genome integrated reporter containing an estrogen response element. When low concentrations of TSA or vorinostat were given together with tamoxifen, tamoxifen acted as a transcriptional ER antagonist. Interestingly, at higher concentrations of TSA or vorinostat, the tamoxifen
switched to act as an ER agonist. The authors suggest that this may be due to the inhibition of (an) additional HDAC(s) at higher concentrations, exemplifying the importance of HDAC inhibitor dosage [37]. As described above, treating ER-negative cells with the combination of an HDAC and DNMT (AZA) inhibitor restores expression of ERa mRNA and inhibits tumor growth. In addition, this treatment restores sensitivity to tamoxifen in in vitro models [44]. In another study, Jang et al. provide evidence that ERb plays an important role in the response to tamoxifen. When MDA-MB-231 and Hs578T ER-negative breast cancer cells were treated with TSA, an increase in ERb but not ERa, expression and nuclear import was observed. This was accompanied with increased responsiveness to tamoxifen. Subsequent depletion of ERb by siRNA abrogated
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tamoxifen response in these cells [48]. Furthermore, others have shown that the sensitization of ER-positive but not ER-negative cells to tamoxifen can be triggered through inhibition of HDAC2 [46]. Collectively these studies indicate a highly complex and possibly very distinct interaction between estradiol (and its mediation by aromatase inhibitors) and tamoxifen with HDAC inhibitors. The underlying mechanism to potentiate hormonal therapy or to reverse hormone therapy resistance may vary fundamentally with different classes of HDAC inhibitors, drug concentrations of the inhibitors and the duration of exposure.
8. Recent clinical advances involving HDAC inhibitors in breast cancer Several HDAC inhibitors have been studied in early clinical trials, including breast cancer. As single agents the HDAC inhibitors have shown limited activity in patients with solid tumor malignancies. A Phase II clinical trial evaluating vorinostat as a single agent showed disease stabilization, but no objective responses were seen and the trial was stopped early [76]. Based on preclinical studies from our laboratory and other investigators, we initiated a clinical trial that is currently enrolling patients, combining vorinostat and tamoxifen in women with ER-positive metastatic breast cancer whose tumor progressed during treatment with aromatase inhibitors. Patients may have been treated with tamoxifen during their adjuvant treatment and may have been further exposed to as many as three chemotherapy regimens in the metastatic setting. Enrollment criteria excluded patients with tamoxifen or fulvestrant treatment for metastatic disease, a history of brain metastases or thromboembolic events. A preliminary report of the trial was presented at the American Society of Clinical Oncology. In the first 25 patients, five of 24 evaluable patients (21%) had an objective response by RECIST criteria and 8/24 (33%) had disease stabilization. Four of the five patients received two prior aromatase inhibitors and two received tamoxifen in the adjuvant setting. Additionally, two of the five patients had prior chemotherapy for metastatic disease. Of the patients with stable disease all but one had prior tamoxifen and chemotherapy. Of the 13 patients exhibiting a benefit from the combination treatment, eight patients expressed both ER and PR, while five patients expressed ER but not PR ([73] and www.asco.org/ASCO/ Abstracts+&+Virtual+Meeting/). While preliminary, these results are encouraging as the expected response rate at this stage of disease for tamoxifen alone is less than 10% and the trial examining vorinostat alone elicited no responses. This trial will continue to enroll patients, with completion anticipated by the end of 2008 (www.clinicaltrials.gov). Several additional trials involving the combination of an HDAC inhibitor, including vorinostat (SAHA), panobinostat (LBH589), valproic acid (VPA) or entinostat (SNDX-275) and either tamoxifen, fulvestrant or an aromatase inhibitor, are underway or in planning.
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