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Estrogen Receptors in Colorectal Cancer: Goalkeepers, Strikers, Or Bystanders?

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Estrogen Receptors in Colorectal Cancer: Goalkeepers, Strikers, Or Bystanders? Published OnlineFirst July 27, 2010; DOI: 10.1158/1940-6207.CAPR-10-0132 Perspective Cancer Prevention Perspective on Jin et al., p. 910 Research Estrogen Receptors in Colorectal Cancer: Goalkeepers, Strikers, or Bystanders? Johan Hartman1 and Jan-Åke Gustafsson2,3 Abstract This perspective on Jin et al. (beginning on page 910 in this issue of the journal) discusses the importance of estrogen signaling in colorectal carcinogenesis, with a focus on estrogen receptor β (ERβ), which is the predominant ER in the colorectal epithelium. The importance of ERβ in breast cancer is well described in the literature, and recent studies reveal that ERβ functions similarly in colorectal cancer. The implications of this pathway include new possibilities to treat or prevent colorectal cancer with targeted endocrine drugs and the potential of ERβ as a novel diagnostic tool. Cancer Prev Res; 3(8); 897–9. ©2010 AACR. Introduction er ambiguous role of diet, strong data points to a protective role for female hormones against CRC development. Colorectal cancer (CRC) is widely considered to be a dis- In this issue of the journal, Jin et al. (12) describe a nov- ease of the industrialized world and a consequence of a cer- el mechanism by which estrogens induce mismatch repair tain dietary intake. Based on epidemiologic studies, diets gene expression in colonic epithelial cells in vitro and with substantial amounts of meat and fat traditionally have in vivo. The DNA mismatch repair system is an evolution- been hypothesized to increase CRC incidence, whereas arily conserved system with a key role in recognizing and fruit, vegetables, and fibers have been suggested to protect repairing mismatches generated during DNA replication against CRC (1, 2). In recent years, however, investigators and recombination. Hence, the finding of Jin et al. could have found a poor correlation between diet and CRC inci- be an important explanation for estrogen-mediated pro- dence. Therefore, dietary intake might influence CRC risk tection against colon carcinogenesis. Of interest, hereditary less than previously reported (3). For example, a large nonpolyposis CRC is a result of mutated genes within the meta-analysis by Alexander et al. (4) based on six prospec- mismatch repair system. tive cohort studies found no correlation between either di- We now know that estrogen functions are mediated by etary fats or animal protein and CRC. A meta-analysis by two nuclear receptor subtypes, estrogen receptor (ER) α Koushik et al. based on 14 cohort studies found that fruit and ERβ. These subtypes bind to estrogen response ele- and vegetable intakes were not associated with CRC risk ments as homodimers or heterodimers either directly in overall but might be associated with a lower risk of rectal promoter regions or indirectly through alternative DNA ele- cancer (5). ments such as regions of activator protein 1 or specificity Other etiologic factors could be more important than protein 1 (13, 14). The transcriptional activity of ERs, how- diet in initiating CRC. For example, the Women's Health ever, depends on direct interactions with nuclear receptor Initiative trial highlighted the importance of estrogens cofactors with chromatin-remodeling abilities. Cofactors and hormone replacement therapy (HRT) in CRC (6), could be of two types—coactivators or corepressors. Under and CRC risk is lower in women than in men (7, 8). Women normal conditions, estrogen-bound ERα activates tran- who took HRT for an average of 5.6 years had a 44% lower scription through the recruitment of coactivators. In relative risk of CRC compared with nonusers. This was the tamoxifen-treated breast cancer cells, however, tamoxifen- only positive cancer-related Women's Health Initiative bound ERα inhibits transcription through the recruitment finding on HRT (9); some HRT results involving breast of corepressors (15). ERα and ERβ have different tissue dis- cancer are discussed later (10). Several studies also indicate tributions and are sometimes coexpressed within the same an inverse association between use of combined oral tissue and cell type. ERβ is the only estrogen receptor in the contraceptives and CRC risk (11). Compared with the rath- normal colonic epithelium and declines dramatically in ex- β Authors' Affiliations: 1Department of Oncology, Karolinska University pression levels in CRC cells (16). Furthermore, ER expres- Hospital,Solna,Sweden,2Center for Biosciences and Nutrition, sion decreases in correlation with higher grades of CRC Karolinska Institutet, Huddinge, Sweden and, 3Center for Nuclear (17). Consequently, one could infer that epithelial ERβ is Receptors and Cell Signaling, University of Houston, Houston, Texas responsible for the protective effect of estrogens against co- Corresponding Author: Jan-Åke Gustafsson, Center for Nuclear Receptors and Cell Signaling, 3013 Science and Engineering Research lorectal carcinogenesis. Center, Houston, TX 77204-5056. Phone: 832-842-8803; Fax: 713-743- A similar pattern of ERβ expression occurs in the breast, 0634; E-mail: [email protected]. where ERβ is the only subtype in normal breast epithelial doi: 10.1158/1940-6207.CAPR-10-0132 cells and is downregulated in breast cancer cells. On the ©2010 American Association for Cancer Research. other hand, ERα expression differs between the breast, www.aacrjournals.org 897 Downloaded from cancerpreventionresearch.aacrjournals.org on September 27, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst July 27, 2010; DOI: 10.1158/1940-6207.CAPR-10-0132 Hartman and Gustafsson where it is coexpressed with ERβ in cancer cells, and the disruptors). In recent years, substantial efforts have been colon-rectum, where it is lacking in both the normal epithe- made to identify the adverse effects of xenoestrogens in lium and cancer cells. Most of the numerous in vitro studies the environment and their potential to affect estrogen sig- of human ERβ function have involved breast cancer cells naling in normal physiology. Today, there is a serious con- (18). Based on these studies, one can conclude that ERβ cern that exposure to these substances could affect human has an overall antiproliferative effect, thereby inhibiting health, including the risk of CRC and other cancers. Xenoes- cancer cell proliferation and antagonizing ERα function in trogens comprise a wide range of structurally diverse the breast (19, 20). Because estrogen signaling has such a compounds (26), including the industrial chemicals poly- central role in breast cancer progression, it generally has chlorinated biphenyls and dioxins, which have well-known been thought that estrogens could even initiate breast adverse health effects and potential to disrupt estrogen- cancer. Nevertheless, HRT with estrogen alone did not in- signaling, and pesticides such as chlordecone, which have crease the risk of breast cancer in the Women's Health Ini- a strong carcinogenic effect. Little is known, however, about tiative clinical trials program (21). the potential role of xenoestrogens in CRC initiation. As mentioned above, colorectal normal or cancer epithe- Phytoestrogens are a diverse class of natural compounds lium does not coexpress ERα and ERβ, and thus, does not with structural similarity to estradiol. These compounds allow any possibilities for ERβ to antagonize ERα function generally have a binding preference for ERβ over ERα. through heterodimerization. One could therefore expect a Several phytoestrogens such as the isoflavone genistein, different expression profile and mechanism of ERβ-mediated however, have ER-independent effects as well and should transcriptional regulation in colorectal normal or cancer not be considered as ERβ-specific ligands. High phytoestro- cells. Our group recently used lentiviral transduction of gen intake has long been associated with a lower incidence an ERβ expression vector to characterize ERβ function in co- of CRC. Few clinical trials, however, have tested this hy- lon cancer cells (22). ERβ expression resulted in the inhibi- pothesis. Fruits, vegetables, and other foods considered rich tion of proliferation and G1 phase cell-cycle arrest, and this in phytoestrogens contain different types and different le- effect depended on a functional DNA-binding region with- vels of phytoestrogens, and therefore, it is difficult to draw in ERβ. We also observed that ERβ expression strongly in- conclusions concerning the significance of individual phy- hibited cMyc and tumor growth in a xenograft mouse toestrogens and CRC. Barone et al. recently found that two model. These data suggest that induced ERβ in CRC cells ERβ-selective phytoestrogens effectively counteracted CRC has an antiproliferative, tumor-suppressive function that tumorigenesis and surprisingly increased ERβ expression in is independent of ERα. This conclusion raises the important mice with mutations of the tumor-suppressor gene adeno- question of whether ERβ could be activated in a more spe- matous polyposis coli (APC; ref. 27). Other tumor models cific manner to prevent CRC carcinogenesis and even re- show similar effects of phytoestrogens. Treatment with phy- press CRC progression? Perhaps this effect could be toestrogen dietary soy isoflavones of an azoxymethane- achieved by using synthetic, ER subtype–specific ligands. induced colon cancer in rats reduced the burden of and The selective ER modulators are a class of synthetic ER increased ERβ expression within the tumor (28). ligands with tissue-specific pharmacology. Tamoxifen is We can conclude
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