Estrogens, MSI and Lynch syndrome-associated tumors

Biochimica et Biophysica Acta 1796 (2009) 194–200

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Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a c a n

Review

Estrogens, MSI and Lynch syndrome-associated tumors Ana Monteiro Ferreira a,b, Helga Westers a, André Albergaria b,c, Raquel Seruca b,d, Robert M.W. Hofstra a,⁎ a

Department of Genetics, University Medical Center Groningen, University of Groningen, PO BOX 30.001, 9700 RB Groningen, The Netherlands Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal c Life and Health Science Research Institute (ICVS), Health Science School, University of Minho, Braga, Portugal d Faculdade de Medicina da Universidade do Porto, Portugal b

a r t i c l e

i n f o

Article history: Received 25 February 2009 Received in revised form 18 June 2009 Accepted 18 June 2009 Available online 25 June 2009 Keywords: Estrogen Estrogen-receptor pathway Lynch syndrome Mismatch repair system Microsatellite instability

a b s t r a c t Estrogens play a major role in the biology of hormone-responsive tissues but also in the normal physiology of various non-typical hormone-responsive tissues. In disease, estrogens have been associated with tumor development, in particular with tumors such as breast, endometrium, ovary and prostate. In this paper we will review the molecular mechanisms by which estrogens are involved in cancer development, with a special focus in Lynch syndrome related neoplasia. Further, we discuss the role estrogens might have on cell proliferation and apoptosis, how estrogens metabolites can induce DNA damage and we discuss a possible connection between estrogens and changes in DNA (hypo- and hyper) methylation. In this review we will also address the protective effect that high levels of estrogens have in MMR related neoplasias. © 2009 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . Estrogens as a carcinogen . . . . . . . . . . . . . Association between low levels of estrogens and MSI 3.1. Lynch syndrome-associated MSI tumours . . 3.2. Estrogens and MSI . . . . . . . . . . . . . 4. Estrogens, mismatch repair and cancer. . . . . . . 5. Estrogens and endometrial cancer . . . . . . . . . 5.1. Tamoxifen, estrogens and endometrial cancer 6. Estrogens and colon cancer . . . . . . . . . . . . 7. Estrogens and known cancer-related pathways . . . 8. Co-activators and repressors of ER . . . . . . . . . 9. General conclusions. . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . in Lynch syndrome-associated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The most common types of cancer worldwide occur in hormonally responsive tissues, such as breast, endometrium, ovary and prostate. Tumors occurring in these tissues show strong associations with the exposure to exogenous or endogenous steroidal hormones. Estrogens are a group of steroid compounds which are present in both men and women; however, their levels are significantly higher in

⁎ Corresponding author. Tel.: +31 50 3617100. E-mail address: [email protected] (R.M.W. Hofstra). 0304-419X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2009.06.004

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women of reproductive age. There are three types of estrogens of which 17β-estradiol is the most potent one as it has the highest affinity for its receptors. It is produced in high amounts in premenopausal women by the ovary. The second endogenous but less potent estrogen is estrone. It is produced from androstenedione, the immediate precursor of estrone. The third estrogen is estriol, a metabolite of estradiol. It is mainly produced by the placenta during pregnancy and is found in lower concentrations than estradiol and estrone in non-pregnant women [1]. Estrogens act through the estrogen receptors (ERs). ERs are ligandactivated transcription factors that have several domains that can bind estrogens and activate transcription of several estrogen-responsive

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genes (see Fig. 1) [2]. There are two receptor isoforms, ERα and ERβ [3,4]. When estrogens binds to these receptors, the receptors dimerize, go to the nucleus and bind to specific DNA sequences, the consensus estrogen response elements (EREs) of ER-responsive genes [5]. The receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers [6]. The activation of ER is influenced by a set of different co-activators, enzymes, and co-repressors. These factors influence the assembly of the transcriptional complex and the subsequent transcription of the ER-responsive genes. This is called ‘the canonical pathway’ of ER. A ‘non-canonical’ pathway of ER has also been described, in which genes are activated without having ERE-like sequences. This nonclassical mechanism accounts for the transcriptional activation of approximately one-third of all estrogen-responsive genes [7]. Alternative mechanisms without DNA binding have also been described. DNA binding proteins such as specificity protein 1 (SP1) are activated by the direct binding of ER [8], for a schematic representation see Figs. 1 and 3. Estrogens play a major role in controlling the menstrual cycle, pregnancy, thus female reproduction. However, estrogens are not only important for the biology of hormone-responsive tissues but they also play an important role in bone strengthening, cholesterol metabolism, and influence the central nervous system and, are also important in the gastrointestinal physiology [9,10]. On one hand ER signaling plays an important role in many normal physiological processes, on the other hand several studies have also shown that estrogens and its metabolites are involved in tumor development. In this review we will address the different possible mechanisms by which estrogens can be involved in tumor development and in particular, we will focus on how the hormone can be involved in the development of Lynch syndrome related neoplasias showing microsatellite instability. 2. Estrogens as a carcinogen For a long time sex hormones have been implicated in various human cancers, such as breast, endometrial, prostate and other cancers. Estrogens in particular are described as being associated with breast cancer since the early thirties of the past century [11]. Even

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before estrogens were discovered, their effects were reported. It was for instance reported that nuns were at higher risk of breast cancer compared to other women and this was linked to nulliparity [12], a condition that results in longer exposure to estrogens during life. Menopausal women, with lower levels of estrogens, were also observed to develop slower the disease than pre-menopausal women, and in 1896 Beatson [13] even suggested surgical castration as a treatment available for patients with breast cancer (ICMR bulletin, 2003 [14]). Also very early, a similar association between estrogens and uterine cancer was described [15]. In 1987 it was recognized and published by the International Agency for Research on Cancer (IARC) that elevated concentrations of estrogens lead to an increased risk of breast and uterine cancers [16]. However, only in 2006 Russo and Russo described in vivo malignant transformation of human breast epithelial cells by estrogens [17]. Salama et al. in 2008 showed that catecholestrogens induce oxidative stress and malignant transformation of human endometrial glandular cells [18]. These and many other studies point towards a direct link between cancer initiation and estrogens. However, how estrogens contribute to cancer is not yet clear. Several possible molecular mechanisms have been put forward to explain the link between estrogens and cancer (see Fig. 2): 1) Estrogens promote cell proliferation via ER-mediated signaling, both through genomic and non genomic pathways, which promotes cell proliferation and growth, and reduces sensitivity to apoptosis. For instance, estrogens stimulated ERs which then can up-regulate WNT1 expression, which causes the tumor to resist going into apoptosis [20]. 2) Another possibility is that estrogens promote signaling via cell membrane-related but ER-independent phosphorylation of target genes. Examples are the phosphorylation of AKT and ERK by estrogens in ER negative cells [21,22]. 3) Estrogens lead to the production of toxic species that are able to induce tumor development. Estrogens are converted to catecholestrogens by cytochrome P450-mediated hydroxylation. Catecholestrogens, specifically the 4-hydroxylated steroids, and their semiquinone and quinone reactive intermediates are considered

Fig. 1. Mechanisms of action of estrogens.

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Fig. 2. Model for the role of estrogens in the progression of microsatellite unstable tumors.

carcinogenic [23]. Various types of damage are found associated with either estrogen quinones binding covalently to DNA or by free radical action. Aneuploidy, gene amplification, arrest of DNA replication as a result of estrogen–DNA adduction, single strand breaks, microsatellite instability, small insertions, and deletions are all examples of these types of DNA damage [9,24,25]. 4) Estrogens are found associated with changes in the methylation status, both hypo- and hyper-methylation of DNA. An example of an estrogen-related hypomethylated gene is PAX2 [26]. An example of an estrogen-related hypermethylation gene is the estrogen receptor gene and MLH1 [27,28]. The last example is particularly interesting, since in this review we focus on MMR related neoplasia.

in Lynch syndrome, almost all patients develop colorectal cancer, followed by endometrium cancer. The cumulative life time risk of endometrial cancer in Lynch syndrome is estimated to be between 20 and 70%, depending on the type of MMR mutation (for a review on this see Vasen [29]). Although MSI is the major characteristic of Lynch syndrome patients, it is also found in 15–25% of sporadic colorectal, endometrial and gastric tumors [30]. MSI is defined by the accumulation of insertions and/or deletions at short DNA repeats (microsatellites), leading to different lengths of the repeat. Accumulation of such mutations in coding mononucleotide repeats of genes with important regulatory functions, e.g. tumor-suppressor genes, but also point mutations in tumor suppressor genes and oncogenes, are thought to be key events in the development of MSI tumors.

What also is believed to have a significant effect on cell growth and tumor formation is the balance between ERα and ERβ [19]. The activation of ERα is associated with increasing cell proliferation whereas ERβ promotes apoptosis. For instance in endometrial cells it was shown that a down regulation of ERα results in a reduction of cell proliferation, an effect that was not seen when ERβ is blocked.

3.2. Estrogens and MSI

3. Association between low levels of estrogens and MSI in Lynch syndrome-associated tumors 3.1. Lynch syndrome-associated MSI tumours Several studies have shown that there is an association between estrogen exposure and the presence of microsatellite instability in tumors. Microsatellite instability (MSI) is a hallmark of tumors from patients with Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). This inherited cancer syndrome is characterized by the development of colorectal cancer (CRC), endometrial cancer and various other cancers and is caused by a mutation in one of the mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2. Colorectal cancer is the most common cancer found

Notarnicola et al. [31] described a significant association between MSI and ER status in colorectal tumors. Interestingly, they verified that MSI tumors harbored low levels of ER expression. Moreover, the withdrawal of estrogens also resulted in an increasing risk of MSI CRC tumors. An interesting hypothesis was made by Breivik et al. [32] by linking estrogens to gender differences in CRC through a mechanism involving MSI [32]. The presence of low levels of ERs can be linked to hypermethylation of the estrogen receptors [27]. However, the mechanism linking estrogens to ER methylation and to MSI is not yet known. Since ER inactivation is due to hypermethylation in 90% of colon cancers [33], it was hypothesized that estrogens affect DNA methylation in general [27]. In fact, it was suggested that estrogens might be key factors in the development of the CpG island methylator phenotype (the CIMP phenotype) [34,35], a phenotype commonly present in many different tumor types. In CIMP tumors, hypermethylation of promoter regions of regulatory genes, such as tumorsuppressor genes, is a general feature. This CIMP phenotype might be the missing link between estrogens and the hypermethylation of

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the ERs and the MSI phenotype, as MSI in the sporadic tumors mostly is caused by hypermethylation of the MLH1 promoter. Besides global hypermethylation (CIMP phenotype), global hypomethylation of introns and coding sequences of genes is also observed in tumors. In CRC, 35%–60% of the cases show reduction of methylation [36]. An example of a gene that is hypomethylated in estrogen-responsive tumors is PAX2 [26]. This is corroborated by in vitro and animal studies that showed that estrogens lead to a decreased DNA methylation of specific genes and are able to restore protective methylation patterns [35].

nopausal women. Clearly the interplay between these two hormones is important [41–43]. Interestingly, the profile of estrogens and metabolites present in these tumors seems to play an important role in the mechanism leading to endometrial cancer. Different rates of the different possible metabolites of estrogens are associated with different effects on the endometrium, and thus carry different risks of developing endometrial cancer [44].

4. Estrogens, mismatch repair and cancer

Besides estrogens, also tamoxifen can be associated with cancer development, in particular endometrial cancer. Tamoxifen is a drug used as adjuvant treatment of ER-positive breast cancer. It acts as an estrogen antagonist in those tumors, reducing tumor growth. However, it was shown that it acts as estrogen agonist in other tissues such as bone, where it prevents osteoporosis [45,46]. In the endometrium it induces cell proliferation. An increased risk of developing EC is reported for postmenopausal women undergoing tamoxifen therapy [47]. The working mechanism of tamoxifen is binding of the compound to ERs and inducing a tamoxifen-specific signaling (see Fig. 3). This signaling probably depends on the serum level of estrogens, closely linked to the menopausal status (more than on menstrual status) of the patient, the ratio between ERα and ERβ, and on the expression of the co-activators and co-repressors, all of which might be tissue-specific.

Slattery et al. [27] raised the idea that at least one of the major MMR genes is estrogen-responsive and that loss of estrogens results in loss of DNA mismatch repair capacity. Wada-Hiraike et al. [37] reported a direct interaction between ER and the MMR gene, MSH2, from immunoprecipitations and pull down assays. In fact the authors suggested that MSH2 is a potent co-activator of ERα. An interesting possibility arose from this study: common co-activators of ER and even ER itself might have a functional role in DNA MMR. Miyamoto et al. [38] demonstrated that cells under a high-level estrogen environment have increased levels of both MLH1 and MSH2 proteins. Moreover, it was observed by the same authors that MLH1 and MSH2 expression is up-regulated and MMR activity was increased by estradiol treatment mediated by the ER pathway [38]. The higher MMR activity would ideally compensate the replication errors occurring at a highly proliferative stage. Lower MMR activity would then also explain the occurrence of endometrial carcinogenesis in a less proliferative stage, when the estrogens levels are low, as in postmenopausal women. These data support all the association between estrogens and MMR, suggesting an estrogen-mediated transcriptional activation of the MMR complex protein. In summary, both studies show a positive correlation between estrogens and MMR activity. So high levels of estrogen give rise to higher cell proliferation and the system seems to protect itself against DNA damage by activating the MMR system. Thus estrogens may initially protect against cancer by activating the MMR system. However, when the MMR system is deregulated, for instance, by hypermethylation of the MLH1 gene, this protective mechanism is lost. It is also interesting to note that tumors of the endometrium are seen mostly in postmenopausal women, women who have low levels of estrogens. 5. Estrogens and endometrial cancer Endometrial cancers (EC) can be divided in two classes, an estrogen-associated type and a non-estrogen-associated type. The first group, to which all MSI-high endometrium tumors belong, is called type I EC. These tumors are found in women with long term exposure to estrogens due to nulliparity, early menarche, late menopause or the use of estrogen replacement therapy. Obesity is also considered a major risk factor, as adipose tissue gives rise to a higher estrogen concentration [13]. About 80% of all endometrial carcinomas are estrogen-associated carcinomas [39,40]. It is in this context important to realize that estrogens do not work on their own. For instance it was shown by the Women's Health Initiative [41–43] that women receiving estrogen in combination with progesterone (progestin) have an increased risk of invasive breast carcinoma. Women receiving estrogen alone (as replacement therapy) did not exhibit an increased risk of breast carcinoma. By contrast, the risk of endometrial carcinoma did increase with estrogen replacement therapy, while progesterone reduces the risk of endometrial carcinoma. The fact that EC are detected mostly in postmenopausal women might be attributed to the loss of progesterone during menopause (and hence no menstrual shedding) in postme-

5.1. Tamoxifen, estrogens and endometrial cancer

6. Estrogens and colon cancer Expression of ERs has also been demonstrated in non-hormonal responsive tissues, such as the gastrointestinal mucosa and its associated tumors, suggesting that estrogens also have a role in these tissues that were previously not thought of as hormoneresponsive tissues [27,48–50]. All findings in colorectal cancer support the hypothesis that high estrogen levels can have a protective effect in specific phases of life. These findings have been used as an explanation for the gender bias observed in CRC incidence, with women having a lower incidence of the disease than men. Hormonal changes associated with pregnancy [51], and hormone replacement therapy (HRT) have been associated with lower risk of CRC [48,52–54]. Most likely this protective effect of estrogens in CRC largely depends on the ratios of receptor α and β. ERβ is the predominant ER isoform in colon tissue and probably the responsible isoform for estrogen transcriptional effects [55–57]. This situation is quite different in breast and endometrium, where ERα is the main isoform present. It has, however, been suggested that ERβ modulates the function of ERα, and that an increased ratio of ERα/ERβ is associated with a progression from a healthy to carcinoma state in those tissues [58]. As for endometrial cancer, the presence of progesterone and the balance between the two hormones is important in CRC protection as well [41–43]. 7. Estrogens and known cancer-related pathways Estrogens can activate proteins other than the ERs. For instance they have been reported to activate the protein kinase A pathway [59], by binding to the G protein-coupled receptor GPR30. Moreover, both insulin-like growth factor 1 (IGF-1) receptor signaling and EGF receptor signaling can be activated by estrogens [60]. Binding of estrogen to these growth receptors leads to dimerization of the receptor, and activation of their kinase activity. Phosphorylation of these proteins leads to activation of downstream signaling pathways, such as the MAPK and PI3K/Atk pathways. The activation of PI3K/Akt pathway has been observed in ER-positive human breast cancer cells [61–66], in rat and mouse endometrial epithelial cells [67,68], and in

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Fig. 3. Estrogen and tamoxifen signaling. Different factors affect the signaling pathway of both ligands in a similar way.

human endometrial cells during the proliferative phase [69]. Activation of PI3K/AKT has been associated with cell survival in a variety of cancers [61,66].

convincingly show the importance of ER cofactors in the development of the tumor type. 9. General conclusions

8. Co-activators and repressors of ER ER-mediated transcriptional regulation depends on the recruitment of co-activators and components of the RNA polymerase II transcription complex, which enhances target gene transcription [70]. Thus, the cellular availability of co-activators and co-repressors is an important determinant in the biological response to both steroid hormone agonists and antagonists in ER-responsive tissues [71]. Many such co-activators and repressors contribute to ER-mediated transcription events. ER-dependent gene transcription frequently depends on the presence of FOXA1. FOXA1 is expressed in the mammary gland, liver, pancreas, bladder, prostate, lung, and colon. Recently, Carroll et al. demonstrated that FOXA1 is required for optimal expression of nearly 50% of ERα-regulated genes and estrogen-induced proliferation, by enhancing binding of ERα to its target genes [72–74]. In the colon, binding of estrogens to ERα induces a cancer promoting response, whereas binding to ERβ seems to exert a protective action [75]. Reasons for this can reside not only in the different expression patterns of ERα and ERβ in vivo but also their need to interact with cellular transcription cofactors which are not functionally equivalent and ubiquitously expressed in all cells [76], highlighting the importance of the ER-co-activators in colon cancer. In endometrium, it has been suggested that co-regulators of ER are involved in tumor progression. It has been proposed that p160 steroid receptor cofactor (SRC) can modulate ER activity and that overexpression of another member of SRC family, AIB1 (Amplified in Breast Cancer 1) in endometrial carcinoma leads to ER increased action and consequent progression to malignancy [77]. Moreover, recently we identified mutations in NRIP1 in MSI-H endometrium tumors in 35% of the investigated tumors (Ferreira AM et al., unpublished data). NRIP1 is a co-repressor of ER signaling. Our data

Estrogens are essential for maintaining of several tissues in humans, but they also play an important role in the carcinogenic process of many different tumor types. Although we know fairly well how estrogens signals, it is still not totally clear how estrogens exerts different effects in different tissues. The differences in the effects of estrogens mentioned in this review in the endometrium and colon may be partly explained by the different physiological roles these organs: the endometrium belongs to the reproductive system, and is a main target of sex hormones, whereas the colon belongs to the digestive system, which is less influenced by sex hormones. Moreover, the regulation of estrogen-responsive genes is different among tissues and is, for example, dependent on the mechanism of action of the ligand or the distribution of ER isoforms alpha and beta and their dimerization [78]. Also the co-activator and co-repressor molecules might exist in different combinations or concentrations among tissues and lead to different results. Furthermore, several ER and non-ER related pathways are now known to activate or be activated by estrogens. These pathways might be affected differently in distinct tissues and therefore have a broad spectrum of influence in tumor formation. Therefore the networks they form with estrogens should not be forgotten, even in tumors occurring in less hormonally-dependent organs. There is still a lot to learn about the possible connection between microsatellite instability (MSI) and estrogens. Estrogens may have a protective effect, which is likely lost after the MMR system has somehow been modulated (mutated). On the other hand estrogens can, by there carcinogenic effect, directly (by mutations) or indirectly (by methylation) inactivate the MMR pathway which results in MSI. MSI can subsequently result in mutations in cofactors or ER signaling which will modulate ER regulated transcription. Clearly the MMR system is a (direct or indirect) target of estrogens, making genes

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involved in the estrogen pathway potential candidates to be studied in MMR-deficient tumors. These findings might also prove useful in the design of novel therapies for such tumors.

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