Steroid receptor coactivator-1: A versatile regulator and promising therapeutic target for breast cancer

Journal of Steroid Biochemistry & Molecular Biology 138 (2013) 17–23

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Review

Steroid receptor coactivator-1: A versatile regulator and promising therapeutic target for breast cancer Yanlei Zhang a,b,1 , Chenyang Duan a,c,1 , Chen Bian a , Ying Xiong a , Jiqiang Zhang a,∗ a b c

Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China Company Ten of Cadet Brigade, Third Military Medical University, Chongqing 400038, China Company Five of Cadet Brigade, Third Military Medical University, Chongqing 400038, China

a r t i c l e

i n f o

Article history: Received 24 November 2012 Received in revised form 6 February 2013 Accepted 19 February 2013 Keywords: Breast cancer Coactivator Steroid receptor coactivator-1 Metastasis Endocrine resistance

a b s t r a c t Breast cancer is the leading cause of cancer death for women worldwide. Various therapeutic approaches have been proposed, among which endocrine therapy has recently become popular due to the high sensitivity of breast tissues to steroids such as estrogens and progesterone. The underlying mechanisms of steroid regulation in breast cancer cell proliferation, invasiveness, metastasis and endocrine resistance, however, remain largely unknown. Steroid receptor coactivator-1 (SRC-1) has attracted much attention because it is an important co-regulator and plays a pivotal role in modulating the transcriptional activities of steroid nuclear receptors. Accumulated research has established a strong correlation between SRC-1 and the pathological progression or disease-related features of breast cancer, which supports its potential as a target for specific therapeutic intervention in the clinical management of breast cancer. In addition, a diverse group of downstream molecules have also been shown to participate in various functional pathways related to SRC-1-associated regulation of breast cancer. These downstream molecules are also considered promising therapeutic targets, providing additional options for targeted treatments. In this review, the expression of SRC-1 in breast cancer and the close relationships between SRC-1 and the cell proliferation, invasiveness, metastasis and endocrine resistance of breast cancer will be discussed, followed by a brief summary of its putative functional mechanisms with an emphasis on the potential therapeutic role of SRC-1. © 2013 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Expression of SRC-1 in breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SRC-1 in the proliferation of breast cancer cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SRC-1 is involved in the metastasis of breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. SRC-1 coactivates the PEA3-mediated expression of downstream molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. SRC-1 partners with CSF-1 and Ets-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. SRC-1 works with AP-1 to enhance the expression of integrin ITGA5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. SRC-1 regulates the expression of the chemokine SDF-1␣ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SRC-1 positively correlates with the endocrine-resistance of breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction ∗ Corresponding author at: 30# Gaotanyan ST, Department of Neurobiology, Third Military Medical University, Chongqing 400038, China. Tel.: +86 23 68752232; fax: +86 23 68752232. E-mail address: [email protected] (J. Zhang). 1 These authors contributed equally. 0960-0760/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jsbmb.2013.02.010

Breast cancer is one of the most common malignant cancers for women and is reported to cause more than 500,000 deaths per year [1]. The mechanisms underlying the cell proliferation, invasion and metastasis of breast cancer are not yet clear. Because breast

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cancer is steroid-sensitive [2–4], great efforts have been made to explore the use of steroids (such as estrogens) or the nuclear receptors of steroids (such as the estrogen receptors (ER) ␣ and ER-␤) as endocrine therapy targets [5]. Selective ER modulators (such as tamoxifen) and aromatase inhibitors (such as anastrozole or letrozole) are the two major endocrine drugs [6,7] that have already been applied as treatments for breast cancer. Tamoxifen is often given to patients with early-stage or metastatic breast cancer; it functions well in ER-positive breast cancers but has no effect on ER-negative breast cancers [7]. Aromatase inhibitors have been demonstrated to be superior to tamoxifen in both efficiency and toxicity and are usually administered in hormone-dependent breast cancer patients [8]. Unfortunately, both of these therapies are not always effective even cause serious side effects under some conditions. For example, aromatase inhibitors administration could not prevent tumour recurrence frequently [6]; tamoxifen may cause cognitive deficiency because estrogens have been shown to target brain regions that related to learning and memory as well as cognitive behavior [9]; it could also be estrogenic instead of antiestrogenic [10] thus increase the risk of endometrial cancers and thrombosis [7,11]. It has been established that the transcriptional activity of nuclear steroid receptors requires their coactivators, among which the p160 steroid receptor coactivator (SRCs) family has been widely studied in recent years. This family contains three members: SRC1, -2 and -3. They share overall 50–55% sequence similarity and 43–48% sequence identity; all of them have 5 domains and the relatively conserved central region contains three LXXLL (L, leucine; X, any amino acid) motifs which is responsible for interaction with ligand-bound nuclear receptors (NRs); distinct LXXLL motifs and contextual sequences exhibit differential binding affinity for different NRs [12]. Accumulated studies have indicated the different but important roles of SRC-1, SRC-2 and SRC-3 respectively in regulating not only a range of physiological activities but also many pathological processes [13,14]. For instance, SRC-1 is suggested to play important roles in the physiology of the central nervous system such as the synaptic plasticity, as suggested in our previous studies [15–19], SRC-2 is demonstrated to function mainly in the metabolism-related events, and SRC-3 is validated to be a possible biomarker for many kinds of cancers including breast cancer, prostatic cancer [12,20]. SRC-1 was first cloned by Onate et al. [21] and is the auxiliary activation factor for many types of nuclear receptors [22]. SRC-1 has since been demonstrated to interact with steroid receptors in a steroid-dependent way, thereby initiating and promoting their regulation in the transcription of targeted genes [23,24]. To date, strong correlations between SRC-1 and the development, progression and even disease-free survival of breast cancer have been identified [25,26]. In this review, the versatile roles of SRC-1 in regulating the cell proliferation, metastasis and endocrine resistance of breast cancer will be highlighted, followed by a brief summary of its multiple underlying signalling pathways.

2. Expression of SRC-1 in breast cancer The development of a normal mammary gland is highly dependent upon the regulation of steroids, and SRC-1 has been established to have low expression in normal mammary glands, but plays important roles in the elongation, branching and density of the normal mammary duct [14]. Decreased expression of SRC-1 is reported to give rise to a reduced ductal density and significantly less ductal branch occupation in the fat pad area [14] as well as decreased number and size of alveoli [14,27,28], suggesting SRC-1 is necessary for the development of normal alveoli following pregnancy.

Berns et al. reported high levels of SRC-1 mRNA in normal breast tissue [29], but later studies in which the protein level of SRC-1 was investigated indicated that SRC-1 protein was very low in normal mammary gland ductal epithelial cells [14,30] and were dramatically increased by approximately 19–29% in breast cancers [31,32]. The abnormal protein expression of SRC-1 has also been correlated with many molecular features and pathological events of breast cancer [13,14,31,33]. For example, the increased SRC-1 protein is correlated with breast cancer cell proliferation, metastasis, human epithelial receptor 2 (HER2) positivity, tumour grading, diseasefree interval [31–34], which will be discussed in more detail in the following sections. Interestingly, one study showed that in ER negative breast cancers, SRC-1 was linked to early relapse and death [13]. Another study also reported that SRC-1 was negatively associated with disease-free survival, positively correlated with HER2 expression and inversely associated with ER-␤;, which has been identified as a marker for increased disease-free survival [35]. Therefore, the level of SRC-1 in breast tissue may serve as a potential diagnostic factor because it is low under physiological conditions but dramatically increases in breast cancer tissues. Currently, few studies address the mRNA expression of SRC-1 in normal or cancerous breast tissue, so more work is needed to elucidate the correlations between the expression levels of SRC-1 and pathological features such as tumour type, grading, metastasis status, etc. What’s more, the combined diagnostic potentials of the expression patterns of several factors such as SRC-1, HER2, ER-␣ and ER-␤ need further investigation.

3. SRC-1 in the proliferation of breast cancer cells The activity of steroids such as 17␤;-estradiol (E2), their receptors and their receptor coactivators in cancer cell growth and proliferation have been explored extensively in previous studies [2–4]. These have demonstrated that SRC-1-mediated regulation of breast cancer cell proliferation may occur through various mechanisms as shown in Fig. 1. Firstly, SRC-1 has been shown to promote breast cancer cell proliferation by stimulating the function of ER␣ [36], which accounts for the aberrant cell proliferation in about two-thirds of breast cancer cases [37]. The SRC-1/ER-␣ complex is supposed to potentiate E2-stimulated MCF-7 cell growth by enhancing the transcriptional activation of many exogenous and endogenous E2-responsive genes[23,38], including cyclin D1a and Mucin1 (MUC1), which are both overexpressed in breast cancer and involved in the SRC-1/ER-␣-related proliferation-enhancing pathways [26,39]. This complex also promotes cancer cell survival by suppressing TNF-␣-induced apoptosis [38]. Secondly, Kishimoto et al. identified an autocrine mechanism of SRC-1-mediated estrogen-induced cancer cell proliferation [40]. SRC-1 was shown to mediate cancer cell proliferation through the autocrine activity of the growth-stimulatory cytokine stromal cell-derived factor 1 (SDF-1/CXCR12), which is a novel target of ER-␣ and PEA3 action in human breast cancer cells [41,42]. Its receptor, CXCR4, is supposed to be regulated by PEA3 [43]. Thirdly, Myc is one of the most important proto-oncogenes, which is sufficient for regulating cancer cell proliferation [44] and SRC-1 was shown to coactivate the expression of Myc through Ets-2 [6,14,31]. In addition, SRC-1 has also been shown to be involved in the signal transducer and activator of transcription 3 (STAT3) signalling pathway, suggesting its potential involvement in leptin-stimulated breast cancer cell proliferation [45]. Therefore, SRC-1 may play important roles in regulating the proliferation of breast cancer cells through various functional pathways. As shown in Fig. 1, these results support the therapeutic potential of SRC-1 to function as a novel target for breast cancer anti-proliferation therapy.

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Fig. 1. SRC-1 serves as a multifunctional regulator of breast cancer cell proliferation via various signaling pathways. In general, SRC-1 coactivates the transcription factor (PEA3, Ets-2)/nuclear receptor (ER-␣)-mediated expression of many downstream molecules, such as inflammatory factors (TNF-␣ and SDF-1/CXCR4), oncogenes (Myc, cyclin D1a and MUC1), etc., and thereby plays diverse regulatory roles, which will finally enhance breast cancer cell proliferation. The arrows represent activation pathways, the blocked arrow represents an inhibition pathway and the dotted arrows represent signaling pathways that have not been elucidated.

4. SRC-1 is involved in the metastasis of breast cancer The invasion and metastasis of aggressive breast cancer cells constitute the final and fatal pathological events during cancer progression. Unfortunately, limited therapeutic interventions are currently available to treat this final stage of cancer development [46]. Tumour metastasis is composed of several processes, including the epithelial-mesenchymal transition (EMT), tumour microenvironment remodeling, cancer cell local adhesion, cell migration and invasion into the surrounding normal tissues, macrophage recruitment, intravasation of cancer cells into the blood or lymph vessels, cancer cell survival in the circulation, settling and colonization in distant organs and finally the formation of a secondary tumour and the neovasculature supporting the new cancerous growth [47], as illustrated in Fig. 2. Previous studies have identified strong correlations between SRC-1 and the processes of breast cancer metastasis, indicating the potential application of SRC-1 for anti-metastatic therapies. 4.1. SRC-1 coactivates the PEA3-mediated expression of downstream molecules The transcription factor polymer enhancer activator 3 (PEA3) is a downstream MAPK effector [48] that has been shown to mediate and regulate the expression of many molecules such as Twist, which is a transcription factor that is expressed in many types of cancers [49,50] and has been shown to significantly enhance the EMT, migration, invasion, expansion and chemotherapeutic resistance of cancer stem cells [50–53]. It also serves as a negative regulator of ER expression by binding to the ER promoter [54,55]. Using a mouse mammary tumour polyoma virus middle T (PyMT) breast cancer mouse model, Qin et al. demonstrated that SRC-1 promoted the invasion and metastasis of breast cancer by coactivating Twist transcription through an interaction with PEA3 at the proximal promoter of Twist [56]. In addition to Twist, many other molecules associated with the invasiveness and metastasis of breast cancer has also been shown to be regulated by PEA3. Interleukin-8 (IL-8) is a proinflammatory chemokine that plays pivotal roles in tumour angiogenesis and metastasis [57]. Chen et al. determined that both ER-␤; and PEA3 participate in tumour invasion by regulating IL-8 expression

and HER2 was indicated as the upstream molecule of the ER-␤; and PEA3/IL-8 pathways [57]. Angiogenesis, for which vascular endothelial growth factor (VEGF) is regarded as the main stimulus, is a major contributor to tumour metastasis. According to Hua et al., overexpressed PEA3 is also capable of enhancing the transcription of VEGF in human breast cancer cells [58]. Additionally, the SDF1␣/CXCR4 axis has been shown to upregulate VEGF to promote angiogenesis, thus mediating the metastasis of many solid tumours [59,60]. One recent study also supported the role of PEA3 in promoting human breast cancer metastasis by showing that PEA3 enhanced the mRNA level and promoter activity of CXCR4 [43]. Matrix metalloproteinases including MMP-7, MMP-9 and MMP-11, which are essential for the microenvironment remodeling surrounding tumour lesions, are also established to be regulated by PEA3 [43]. Based on the close interactions between SRC-1 and PEA3, the PEA3-mediated expression of IL-8, CXCR4, VEGF and MMPs may define the functional pathways of SRC-1-regulated breast cancer invasion and metastasis (Fig. 2). Taken together, in breast cancer, SRC-1 may regulate metastasis by influencing the EMT and cancer cell migration (Twist), microenvironment remodeling (MMPs), local inflammation and chemotaxis (IL-8, SDF-1␣/CXCR4) as well as angiogenesis (VEGF) that are mediated by PEA3. Many more insights into these complicated signaling pathways are needed to identify potential targeted interventions for breast cancer. 4.2. SRC-1 partners with CSF-1 and Ets-2 Colony-stimulating factor-1 (CSF-1) is supposed to be involved in the recruitment of macrophages, which is an important indicator of metastasis. According to Wyckoff et al., tumour cells express CSF-1 and epidermal growth factor (EGF) receptor, whereas macrophages expressed CSF-1 receptor and EGF [61]. Therefore, CSF-1 from tumour cells recruited macrophages, and EGF from the recruited macrophages promoted the migration, invasion and metastasis of breast cancer. Wang et al. reported that knocking down SRC-1 significantly reduced breast cancer cell intravasation and decreased lung metastasis, so SRC-1 was suggested to coactivate CSF-1 expression and increase macrophage recruitment to the tumour lesions [30], elucidating an inflammation-related pathway for SRC-1-associated breast cancer metastasis.

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Fig. 2. Systematic signaling pathways of SRC-1 functioning in the process of breast cancer metastasis. SRC-1 coactivates the expression of some inflammatory factors (IL-8, SDF-1␣/CXCR4, CSF-1), transcriptive factor (Twist), integrin (ITGA5), growth factor (VEGF), oncogenes (Myc, HER2) and matrix metalloproteinases (MMP-7, MMP-9, MMP-11), and therefore plays pivotal but differential roles in each step of the breast cancer metastasis, including the EMT, microenvironment remodeling, local adhesion, migration, invasion and intravasation of breast cancer cells, local inflammatory events and angiogenesis. The arrows represent activation pathways, while the dotted arrows represent signaling pathways that have not been elucidated.

Studies also indicated that an SRC-1 deficiency inhibited erythroblast transformation-specific 2 (Ets-2) -mediated HER2 expression. This process may involve the MAPK/AKT pathway as AKT activation was lower in the absence of SRC-1 and Ets-2 is a target of MAPK; when SRC-1 coactivates Ets-2 to regulate HER2, SRC-1 may also activate MAPK signaling [30,62,63]. McBryan et al. elucidated a novel mechanism of aromatase inhibitor-specific metastatic progression, in which the interactions between SRC-1 and Ets-2 play pivotal roles in promoting the dedifferentiation and migration of hormone-dependent breast cancer. In this study, SRC-1 was shown to drive the aromatase inhibitor-specific metastatic progression and was required for the aggressive and motile phenotype of aromatase inhibitor-resistant cells [6]. In addition, the direct physical interactions between SRC1 and Ets-2 regulated Myc and MMP-9, which was correlated with the metastasis and endocrine resistance of breast cancer cells [14,31,64]. To date, the mechanisms governing SRC-1-mediated breast cancer metastasis via its association with Ets-2 and the regulation of various downstream molecules have been identified in a diverse range of studies. SRC-1 may coactivate Ets-2 to promote breast cancer metastasis by regulating the expression of CSF-1, MMP-9, Myc and HER2, and thereby differentially affect local inflammation, surrounding microenvironment remodeling, cancer cell migration, intravasation and invasiveness of breast cancer cells.

4.3. SRC-1 works with AP-1 to enhance the expression of integrin ITGA5 The integrin family is a major contributor to both angiogenesis and inflammation, which are the key events in many types of diseases including cancer and atherosclerosis. Integrins are crucial to cancer metastasis for their contributions to the local adhesion of cancer cells [65]. In both breast cancer cell lines and primary tumours, the downregulation of SRC-1 is shown to significantly reduce the expression of integrin ␣5 (ITGA5) [30,66,67]. SRC-1 deficiency significantly reduced the adhesion and migration capabilities of breast cancer cells, lengthened their focal adhesion times and decreased expression of ITGA5 in ER-negative breast cancer cells [66]. Furthermore, both ITGA5 deficiency and knockdown in SRC-1-deficient or SRC-1-expressing breast cancer cells resulted in disturbed integrin-mediated signaling, including reduced downstream phosphorylation and dampened activation of focal adhesion kinase, paxillin, Rac1, and Erk1/2 during cell adhesion; further experiments demonstrated that SRC-1 promoted the promoter activity of ITGA5 through the activator protein-1 (AP-1)-binding site [66]. Therefore, SRC-1 may promote breast cancer metastasis by directly enhancing ITGA5 expression and thereby inducing the ITGA5-mediated adhesion and migration of breast cancer cells. Whether other members of the integrin family such as the integrin ␣v␤3 are involved

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in SRC-1-related breast cancer metastasis currently remains unknown. 4.4. SRC-1 regulates the expression of the chemokine SDF-1˛ As mentioned above, various studies have reported the SRC-1mediated control of SDF-1␣ in estrogen-induced breast cancer cell proliferation. More specifically, the chemokine SDF-1 and its receptor CXCR4 have also been implicated in the modulation of cancer cell migration and recruitment [41]. Kishimoto et al. elucidated a paracrine mechanism through which the SRC-1-mediated control of SDF-1␣ expression regulates the invasiveness and metastasis of breast cancer cells; the conditioned media from SRC-1-expressing MCF-7 cells also increased the invasiveness of breast cancer cells expressing metastasis-associated genes and CXCR4 [40]. Therefore, the SRC-1-mediated regulation of the SDF-1␣/CXCR4 axis also functions to modulate breast cancer metastasis. In summary, as the coactivator of many types of transcriptional factors, SRC-1 is able to regulate the expression of a diverse group of targeted genes, such as CSF-1, ITGA5, etc., as shown in Fig. 2. These targeted downstream molecules are supposed to be correlated with the EMT, microenvironment remodeling, local adhesion, migration and invasiveness of breast cancer cells and tumour neovascularization, all of which are involved in breast cancer metastasis. These observations indicate the pivotal roles of SRC-1 in the multistep metastatic process, and the regulatory process has also been shown to enhance the invasiveness and metastasis of breast cancer. However, the possible roles of SRC-1 in the survival of breast cancer cells in circulation, settling and colonization at the distant organ remain largely unknown. Many more insights into the versatile roles of SRC-1 may provide new avenues for the early diagnosis and specific treatments of metastatic breast cancer. 5. SRC-1 positively correlates with the endocrine-resistance of breast cancer The acquired resistance to endocrine therapy in breast cancer is still a major challenge, and its mechanisms remain poorly understood. An early study by Xu et al. showed that the loss of SRC-1 function resulted in a partial resistance to hormones [28], suggesting a putative function of SRC-1 in the endocrine-resistance of breast cancer.

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HER2 has been shown to be associated with the progression and endocrine resistance of human breast cancer [68]. It has been found that patients who present HER2 overexpression in combination with SRC-1 manifest a greater probability of recurrence following tamoxifen treatment [68]. The expression of SRC-1 and HER2 is upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors, which may represent an early adaptation of breast cancer cells to estrogen deprivation in vivo [69]. Knowing that expression of HER2 can be mediated by Ets-2, SRC-1 is supposed to influence the endocrine resistance of breast cancer by coactivating Ets-2-mediated expression of HER2. In addition, overexpression of HER2 in ER-positive breast cancer cells has been shown to confer tamoxifen resistance, while its suppression improves the anti-proliferative effects of tamoxifen [70]. HER2 transcription is also directly suppressed by estrogen-ER and tamoxifen-ER complexes [71]. The co-association of SRC-1 and ER-␣ was increased in endocrine-resistant cells after tamoxifen treatment, suggesting that the interactions between SRC-1 and ER-␣ may predict the responses of patients receiving endocrine treatments [67]. Therefore, it should be interesting to investigate whether SRC-1 may work with ER (ER-␣ and ER-␤;) to mediate the expression of HER2 and, thus, regulate the endocrine resistance of breast cancer cells. The direct interaction between SRC-1 and Ets-2 also regulates the expression of the oncogene Myc, which is associated with endocrine resistance [6,64]. Al-Azawi et al. demonstrated that the Ets-2 transcriptional regulation of Myc in breast cancer cells resistant to endocrine treatments was dependent on SRC-1; further explorations also indicated the ability of SRC-1 to utilize Ets-2 to regulate Myc expression. These signaling mechanisms are understood to play important roles in the development of steroid resistant/independent breast cancer [63]. ADAM22 is a non-protease member of the ADAM family, and its expression is increased in endocrine-resistant breast cancers [72,73]. Clinically, ADAM22 is regarded as an independent predictor of poor disease-free survival in breast cancer patients, McCartan et al. identified ADAM22 as a direct ER-independent target of SRC1 and demonstrated its critical role in the SRC-1-mediated switch from a steroid-responsive breast cancer to a steroid-resistant state [74]. These data indicate the potential for ADAM22 to serve as a prognostic and therapeutic target to improve treatments for endocrine-resistant breast cancer.

Fig. 3. SRC-1-related signaling pathways in the endocrine resistance of breast cancer. Each of the mentioned pathways is suggested to have particular effects on regulating the endocrine resistance of breast cancer. The coactivation of HER2 expression is supposed to represent an early adaptation of breast cancer cells to estrogen deprivation. Twist represses the expression of ER-␣ and thereby converts ER-␣-negative breast cancers into ER-␣-positive breast cancers. SRC-1 coactivates Ets-2 to regulate the expression of Myc, and the SRC-1/Ets-2/Myc pathway may play important roles in the development of steroid resistant/independent breast cancer. ADAM22 serves as an ER-independent mediator that plays critical roles in the SRC-1-mediated switch of breast cancers from a steroid-responsive to a steroid-resistant state. SRC-1, HOXC11 and S100␤; are demonstrated to form a novel biomolecular interaction network functioning to drive an adaptive response to endocrine therapy with negative consequences for survival. The arrows represent activation pathways, while the blocked arrow represents an inhibition pathway. The dotted arrows represent signaling pathways that have not been demonstrated.

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McIlroy et al. showed that HOXC11 and SRC-1 concordantly regulate the expression of the calcium-binding protein S100␤ in resistant breast cancer cells [75]. This novel biomolecular interaction network drives an adaptive response to endocrine therapy with negative consequences for survival in breast cancer. PEA3mediated expression of Twist also accounts for the endocrine resistance of breast cancer. A recent study by Fu et al. showed that Twist was inversely associated with ER-␣ expression, which suggests that Twist may serve as a specific target for converting ER␣-negative breast cancers to ER-␣-positive ones in an attempt to restore sensitivity to endocrine therapy with selective ER-␣ antagonists [49]. Determining the roles of crosstalk in the SRC-1/ER-␣ pathway and SRC-1/PEA3/Twist pathway may be a novel challenge for future studies, and investigations of the possible interactions in these corroborative pathways may be of great help to the further elucidate not only breast cancer endocrine resistance but also the pathological progression. In summary, several molecules are involved in endocrine resistance regulatory pathways as shown in Fig. 3. Each of the involved pathways has been shown to have specific effects on the regulation of breast cancer endocrine resistance and all of these molecules may be regarded as potential therapeutic targets for breast cancer. 6. Conclusions Cell proliferation, invasion, metastasis and endocrine resistance are major obstacles in the management of breast cancer. SRC-1 plays a key regulatory role in the various pathological events in breast cancer, which highlights its great potential as a therapeutic target. A diverse group of downstream molecules and coregulators of SRC-1 has been identified, and these factors have important physiological functions during the onset and progression of breast cancer. SRC-1 and these downstream molecules provide more opportunities for the clinical intervention of breast cancer, but many problems remain unexplored. For example, are there other methods that can be used for the safe, quick, accurate and noninvasive detection of SRC-1 in the early diagnosis of breast cancer? The accumulated evidence suggests that SRC-1 may serve as an effective and efficient biomarker for the early detection of and therapeutic intervention against breast cancer, but further efforts are urgently needed to better understand the specific roles of SRC-1 in breast cancer. Our studies indicated that SRC-1 is the predominant coactivator of p160 family in the brain and may function to regulate learning and memory as well as cognition, it is possible that any SRC-1 inhibitor/compound may cause cognitive problem as aromatase inhibitors or tamoxifen do. Therefore, how to make these possible inhibitors/compounds specific against cancer cells but not affect brain function will be a great challenge in the future. Conflict of interest None. Acknowledgments This work was supported in part by the National Science Foundation of China (NSFC, No. 81171035). References [1] C.K. Zoon, E.Q. Starker, A.M. Wilson, M.R. Emmert-Buck, S.K. Libutti, M.A. Tangrea, Current molecular diagnostics of breast cancer and the potential incorporation of microRNA, Expert Review of Molecular Diagnostics 9 (5) (2009) 455–467. [2] J. Kotsopoulos, S.A. Narod, Androgens and breast cancer, Steroids 77 (1-2) (2012) 1–9.

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