The SWI/SNF Chromatin Remodeling Subunit BAF57 Is a Critical Regulator of Estrogen Receptor Function in Breast Cancer Cells

Abstract

Estrogen receptors (ERs) play critical roles in both normal mammary gland development and in the formation and progression of breast tumors, constituting a major therapeutic target for breast cancer treatment. We have previously described that ER transcriptional activity is potentiated by BAF57, a core subunit of the mammalian SWI/SNF chromatin remodeling complex. Here we provide evidence demonstrating an important role for BAF57 as regulator of ER functions in breast cancer cells. Different experimental manipulations leading to the abrogation of BAF57 expression and/or function severely reduced the expression of various endogenous ER target genes and blocked estrogen-stimulated proliferation in ZR-75-1 breast cancer cells. Moreover, using a structure-function analysis, we have defined the protein domains required for the functional interaction between ER␣ and BAF57, including a key region within the hinge of ER␣ that is essential for BAF57 recruitment and its function on ER-mediated transcription. Interestingly, we found that BAF57 is an ER subtype-selective modulator that specifically regulates ER␣-mediated transcription. Taken together, our results suggest that targeting BAF57 could represent a new way to effectively inhibit the action of ER␣.Breast cancer is a leading cause of cancer mortality among Western women with an estimated annual incidence of 1 million cases worldwide (see Ref. 1 and references therein). Estrogen hormones play a critical role in the development and normal physiology of the mammary gland, and, whereas various factors contribute to the etiology of breast cancer, estrogens within the context of other signaling pathways are an important influence in the initiation and progression of breast tumors (reviewed in Ref. 2). Estrogen effects are mediated by the related but distinct estrogen receptors ␣ (ER␣) 2 and ␤ (ER␤), although accumulating evidence suggests that ER␣ is the main transducer of estrogen signals promoting cell proliferation in both normal and cancerous breast tissues (3-5).Estrogens can act through nongenomic pathways, although most described estrogen actions are mediated by ER␣ and ER␤ acting as ligand-dependent transcription factors. Estrogen receptors belong to the nuclear receptor superfamily (6), and they regulate many physiological processes in response to their natural ligand, 17␤-estradiol (E2). Upon ligand binding, ERs bind to specific DNA sequences (EREs) present in the promoters of their target genes, triggering the recruitment of many cofactors that must overcome the barrier to transcription that represents the tightly packed chromatin fiber and recruit basal transcription factors and RNA polymerase II. The chromatin remodeling factors are usually divided into two distinct categories: first those enzymes responsible for the covalent modification of the histones, and second, ATP-dependent protein complexes that modify the location and association of nucleosomes with the DNA. Both classes of chromatin remodeling factors, acting together in a concerted manner, contrib...

SMARCE1 is required for the invasive progression of in situ cancers

“…At a mechanistic level, prior studies of SMARCE1 function have focused on its ability to recruit the SWI/SNF complex to genes regulated by hormone receptors (22)(23)(24). However, our ChIP-seq and MS observations indicate that SMARCE1 binds most enhancers in the absence of hormone receptors and the SWI/SNF complex, indicating that both are dispensable for SMARCE1's regulatory functions in invasive cells.…”

Recruitment of the SWI/SNF Chromatin Remodeling Complex to Steroid Hormone-regulated Promoters by Nuclear Receptor Coactivator Flightless-I

“…8C). This result was unexpected given the previous demonstrations that various subunits of the SWI/SNF complex can interact with ER␣ and with the glucocorticoid receptor (6,7,(33)(34)(35)(36) and the implicit assumption that these interactions were responsible for recruitment of SWI/SNF to steroid hormone responsive promoters. Although our results demonstrate that Fli-I is required (presumably by bridging ER or ER-associated coactivators to BAF53) for recruitment of SWI/SNF to estrogen-responsive promoters, it is possible that interactions of ER with additional subunits of SWI/SNF also contribute to SWI/SNF recruitment, as discussed further below.…”

Interplay between chromatin remodelers and protein arginine methyltransferases

“…Inactivating mutations and deletion of hSWI/SNF subunits including BRG1, BRM, BAF57, and INI1 have been found in various cancers. Loss of BRG1 and BRM expression have been documented in various tumors of the breast, lung, pancreas, and prostate, while lack of expression of BAF57 has been observed in some breast cancer cell lines (Wong et al, 2000;Decristofaro et al, 2001;Reisman et al, 2003;Garcia-Pedrero et al, 2006;Kiskinis et al, 2006). Similarily, inactivating mutation of INI1 have been linked to malignant rhabdoid tumors, which are lethal childhood tumors that affect kidneys and brain (Versteege et al, 1998).…”