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Mechanisms of Estrogen Receptor Antagonism Toward P53 and Its Implications in Breast Cancer Therapeutic Response and Stem Cell Regulation

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Mechanisms of Estrogen Receptor Antagonism Toward P53 and Its Implications in Breast Cancer Therapeutic Response and Stem Cell Regulation Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation Santhi D. Konduria,1,2, Rajesh Medisettya,1, Wensheng Liua,3, Benny Abraham Kaipparettub,c,4, Pratima Srivastavaa,5, Hiltrud Brauchb,c, Peter Fritzb,c, Wendy M. Swetziga, Amanda E. Gardnerd, Sohaib A. Khand, and Gokul M. Dasa,6 aDepartment of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, NY 14263; bDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, D 70376 Stuttgart, Germany; cUniversity Tuebingen, D 72074 Tuebingen, Germany; and dDepartment of Cancer and Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267 Communicated by Elwood V. Jensen, Vontz Center for Molecular Studies, Cincinnati, OH, June 30, 2010 (received for review June 17, 2010) Estrogen receptor α (ERα) plays an important role in the onset and and greatly contributes to the onset and progression of breast progression of breast cancer, whereas p53 functions as a major cancer (6, 7). tumor suppressor. We previously reported that ERα binds to p53, Similar to ERα, tumor suppressor p53 also plays a central role resulting in inhibition of transcriptional regulation by p53. Here, in many cellular processes, such as cell cycle regulation, apoptosis, we report on the molecular mechanisms by which ERα suppresses senescence, and differentiation (8–10). Although these functions p53’s transactivation function. Sequential ChIP assays demon- of p53 are essential to maintain normal cellular homeostasis, if left strated that ERα represses p53-mediated transcriptional activation uncontrolled, they can lead to deleterious consequences. As such, in human breast cancer cells by recruiting nuclear receptor core- mutations in the p53 gene and aberrations in the p53 signaling pressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). pathway pave the way to tumorigenesis (11). Extensive research RNAi-mediated down-regulation of NCoR resulted in increased over the past two decades has placed p53 at the hub of a very endogenous expression of the cyclin-dependent kinase (CDK)- complex network of signaling pathways that integrate a variety of inhibitor p21Waf1/Cip1 (CDKN1A) gene, a prototypic transcriptional intracellular and extracellular inputs. It is becoming increasingly CELL BIOLOGY target of p53. While 17β-estradiol (E2) enhanced ERα binding to clear that the opposing effects of various components of the p53 p53 and inhibited p21 transcription, antiestrogens decreased ERα signaling network must be carefully balanced to correctly regulate recruitment and induced transcription. The effects of estrogen p53 function and induce the appropriate cellular response (11, 12). and antiestrogens on p21 transcription were diametrically oppo- One such modulator of p53 signaling is ERα. We have reported site to their known effects on the conventional ERE-containing that in ER-positive human breast cancer cells, as well as in a mouse ERα target gene, pS2/TFF1. These results suggest that ERα uses xenograft model, ERα binds to p53 and represses its transcriptional dual strategies to promote abnormal cellular proliferation: en- function (13–15), resulting in inhibition of p53-mediated cell cycle hancing the transcription of ERE-containing proproliferative genes arrest (14) and apoptosis (15). and repressing the transcription of p53-responsive antiprolifera- Compared with many other cancer types, p53 mutations are not tive genes. Importantly, ERα binds to p53 and inhibits transcrip- very frequent in breast cancer. Approximately 80% of breast can- tional activation by p53 in stem/progenitor cell-containing murine cers express wild-type p53. Moreover, 70–80% of breast cancers are mammospheres, suggesting a potential role for the ER–p53 inter- also ER-positive, and the majority of these express wild-type p53, action in mammary tissue homeostasis and cancer formation. albeit functionally debilitated. Interestingly, most ERα-negative Furthermore, retrospective studies analyzing response to tamoxi- breast tumors express mutant p53 (16–18). Therefore, it is likely fen therapy in a subset of patients with ER-positive breast cancer that abrogation of the p53 signaling pathway is a major event in expressing either wild-type or mutant p53 suggest that the pres- both ERα-positive and -negative tumors; in the former, wild-type ence of wild-type p53 is an important determinant of positive p53 is functionally repressed by ERα, and in the latter, p53 is therapeutic response. inactivated by mutations. ERα is the primary target of endocrine therapy in breast cancer. However, a major clinical obstacle is that nuclear receptor corepressor | mammary epithelial cells | mammospheres | a large fraction of patients with ERα-positive breast tumors do not tumor suppressor protein | tamoxifen therapy respond to tamoxifen therapy (19–21). The presence of wild-type p53 has been reported to have a positive impact on the therapeu- ells integrate multiple pathways to elicit responses to various tic response and prognosis of breast cancer patients (17, 22–24). Csignals, depending on the cellular context and tissue micro- environment. Estrogen receptor α (ERα) is a ligand-dependent transcriptional regulator that, when bound to estrogen response Author contributions: S.D.K., R.M., W.L., B.A.K., H.B., S.A.K., and G.M.D. designed re- elements (EREs) on target gene promoters, regulates transcription search; S.D.K., R.M., W.L., B.A.K., P.S., P.F., W.M.S., and A.E.G. performed research; S.A.K. contributed new reagents/analytic tools; S.D.K., R.M., W.L., B.A.K., H.B., S.A.K., via estrogen-dependent recruitment of steroid receptor coac- and G.M.D. analyzed data; and G.M.D. wrote the paper. tivators (SRCs), such as SRC1, SRC2/DRIP1/TIF2/NCoA2/, and The authors declare no conflict of interest. SRC3/AIB1/TRAM1/pCIP/RAC3/ACTR, followed by chromatin 1 – S.D.K., and R.M. contributed equally to this work. histone acetylation (1 3). On the other hand, when antiestrogens 2 α Present address: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, such as tamoxifen are bound to ER ,variouscorepressors,in- FL 32827. cluding nuclear receptor corepressor (NCoR) and silencing medi- 3Present address: Department of Pediatrics, State University of New York, Buffalo, NY 14214. ator for retinoid and thyroid hormone receptors (SMRT), are 4Present address: Department of Molecular and Human Genetics, Baylor College of Med- recruited. This is followed by recruitment of histone deacetylases icine, Houston, TX 77030. α (HDACs), leading to transcriptional repression (4, 5). ER sig- 5Present address: Department of Drug Metabolism and Pharmacokinetics, Lupin Research naling plays an important role in many tissues, including the Park, Pune 411042, India. mammary gland, where its expression is required for normal gland 6To whom correspondence should be addressed. E-mail: [email protected]. development and the preservation of adult mammary gland func- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tion.Whenderegulated,ERα becomes abnormally proproliferative 1073/pnas.1009575107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1009575107 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 However, the cellular and molecular mechanisms by which p53 Importantly, HDAC1 was present in the p53/ERα/NCoR/SMRT influences endocrine therapy efficacy remain elusive. complex on the p21 promoter (Fig. 1A). NCoR, SMRT, and Recent progress in the identification and characterization of HDAC1 were not recruited to the p21 promoter when ERα was normal and tumor stem and progenitor cells in murine and human knocked down, suggesting that ERα is required for their re- mammary gland tissue has triggered an intense effort to explore the cruitment (Fig. 1B). ERα knockdown did not affect NCoR, mechanisms that regulate the balance between symmetric and SMRT, or HDAC1 protein expression levels (Fig. 1C) but, as asymmetric division of these cells (25, 26). Disabling p53 increases expected, resulted in the loss of ERα on the promoter (Fig. 1D), stem cell production by favoring symmetric division over asymmetric further supporting the role of ERα in recruiting the corepressors division, suggesting an important role for p53 in mammary tissue and HDAC1 to the p21 promoter. Treatment with E2 enhanced homeostasis and cancer formation (25). Importantly, a fraction of the recruitment of HDAC1 and NCoR to the p21 promoter mammospheres derived from normal murine and human mammary but did not affect SMRT recruitment (Fig. 1E). Furthermore, tissue and breast cancer tissue display stem/progenitor cell char- knocking down NCoR resulted in transcriptional activation of an acteristics and express ERα (27–29). However, whether ERα dis- exogenously transfected p21 promoter plasmid (Fig. 1F) and ables wild-type p53 in these cells remains to be elucidated. increased endogenous expression of p21 mRNA and protein In the present study, we examined the mechanisms by which (Fig. 1 G and H). Collectively, these data suggest that ERα- ERα binds to p53 on p53 target gene promoters and represses mediated inhibition of p53 transcriptional activity is NCoR-de- p53-mediated transcriptional activation. We provide evidence pendent. Furthermore, the importance of NCoR in the ERα–p53 that ERα recruits corepressors when bound to p53 and show that repressor complex is strengthened
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