Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation

Abstract

Estrogen receptor α (ERα) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ERα binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ERα suppresses p53's transactivation function. Sequential ChIP assays demonstrated that ERα represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor corepressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)-inhibitor p21 Waf1/Cip1 (CDKN1A) gene, a prototypic transcriptional target of p53. While 17β-estradiol (E2) enhanced ERα binding to p53 and inhibited p21 transcription, antiestrogens decreased ERα recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ERα target gene, pS2/TFF1. These results suggest that ERα uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ERα binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER-p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.nuclear receptor corepressor | mammary epithelial cells | mammospheres | tumor suppressor protein | tamoxifen therapy

Estrogen receptor prevents p53-dependent apoptosis in breast cancer

“…ER binding by fulvestrant both blocks the agonist effects of E2 and leads to degradation of the ER through an ubiquitin-mediated mechanism (8)(9)(10). Although fulvestrant has activity in some women with tamoxifen-resistant disease, resistance to fulvestrant also limits its utility (11).…”

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

“…ChIP assays were performed as per the manufacturer's instructions (Upstate, Lake Placid, NY, USA) with minor modifications (49,52,53,56,57). Cell lysates (400 μL) were sonicated 25 times, alternating each 10 sec pulse with 20 sec gaps (Misonix Inc., Farmingdale, NY, USA).…”

“…Our previous data shows that ERα uses a dual strategy to promote abnormal cellular proliferation in breast cancer: repressing the transcription of p53-responsive genes and enhancing the transcription of ERE-containing proproliferative genes (49). To date, the potential mutual interrelationship between MGMT and ERα (and the link to p53) has not been explored in drug-(tamoxifen) resistant breast tumors.…”

Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics

“…While ERs are master regulators essential for development and maintenance of normal sexual and reproductive functions, they can also play a role in the cardiovascular, musculoskeletal, immune and central nervous systems. [8][9][10] These two diverse networks exhibit crosstalk that can be due to direct interaction between p53 and the ERs, with the more frequently described outcome being repression of p53 activity, [11][12][13][14] although p53 can also inhibit ERα. 15,16 The inhibitory crosstalk, which can be mediated by physical interactions between the two proteins, can be relieved by stress-dependent post-translational modifications of p53.…”