Anti-proliferative effect of estrogen in breast cancer cells that re-express ERα is mediated by aberrant regulation of cell cycle genes

Abstract

Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. The re-expression of ERalpha in ER-negative MDA-MB-231 breast cancer cells has been used as a model system, in which hormone-dependent responses can be restored. Paradoxically, in contrast to the mitogenic activity of 17beta-estradiol (E2) in ER-positive breast cancer cells, E2 suppresses proliferation in ER-negative breast cancer cells in which ERalpha has been re-expressed. We have used global gene expression profiling to investigate the mechanism by which E2 suppresses proliferation in MDA-MB-231 cells that express ERalpha through adenoviral infection. We show that a number of genes known to promote cell proliferation and survival are repressed by E2 in these cells. These include genes encoding the anti-apoptosis factor SURVIVIN, positive cell cycle regulators (CDC2, CYCLIN B1, CYCLIN B2, CYCLIN G1, CHK1, BUB3, STK6, SKB1, CSE1 L) and chromosome replication proteins (MCM2, MCM3, FEN1, RRM2, TOP2A, RFC1). In parallel, E2-induced the expression of the negative cell cycle regulators KIP2 and QUIESCIN Q6, and the tumour-suppressor genes E-CADHERIN and NBL1. Strikingly, the expression of several of these genes is regulated in the opposite direction by E2 compared with their regulation in ER-positive MCF-7 cells. Together, these data suggest a mechanism for the E2-dependent suppression of proliferation in ER-negative breast cancer cells into which ERalpha has been reintroduced.

Estrogen receptor α (ESR1) over-expression mediated apoptosis in Hep3B cells by binding with SP1 proteins

“…Similar results were observed while inducing the overexpression of ERa in ERa-negative breast cancer cells (Tolhurst et al 2011). It has been reported that in ER-negative MDA-MB-231 breast cancer cells re-expression of ERa results in the suppression of proliferation by E 2 (Moggs et al 2005).…”

Interplay between chromatin remodelers and protein arginine methyltransferases

“…When PRMT5 is knocked down growth and proliferation of transformed lymphoma cell lines is inhibited (Pal et al, submitted for publication). Role of PRMT5 in tumorigenesis is further supported by the observation that PRMT5 is overexpressed in gastric carcinoma and that suppression of ER negative breast cancer cell proliferation following 17-b-estradiol treatment was accompanied by suppression of PRMT5 expression (Kim et al, 2005;Moggs et al, 2005). These studies suggest that increased expression of PRMT5 is part of the mechanism by which cells become transformed.…”

Gene expression profiling reveals that the regulation of estrogen-responsive element-independent genes by 17β-estradiol-estrogen receptor β is uncoupled from the induction of phenotypic changes in cell models

“…To accomplish this, we generated an ERE-binding defective ERb mutant (ERb EBD ) which renders the receptor nonfunctional at the ERE-dependent pathway, while conserving the regulatory potential at the ERE-independent pathway. We used ER-negative cells as experimental models, with which exogenously introduced ERs were shown to regulate the expression of responsive genes (Licznar et al 2003, Kian Tee et al 2004, Stossi et al 2004, Moggs et al 2005, Monroe et al 2005 and to induce phenotypic changes (Garcia et al 1992, Jiang & Jordan 1992, Zajchowski et al 1993, Lazennec & Katzenellenbogen 1999, Lazennec et al 2001, Licznar et al 2003. In adenovirus-infected cells, we found that genomic responses induced by ERb EBD in response to a physiological level of E 2 are insufficient to alter cellular proliferation, death, or motility, in contrast to E 2 -ERb.…”

“…To ensure that ERb EBD can indeed discriminately regulate endogenous gene expression, we used MDA-MB-231 cells as a model within which exogenously expressed ERs were shown to induce gene expressions that affect phenotypic characteristics (Garcia et al 1992, Jiang & Jordan 1992, Zajchowski et al 1993, Lazennec & Katzenellenbogen 1999, Lazennec et al 2001, Licznar et al 2003, Moggs et al 2005. We also used recombinant adenoviruses for an efficient gene delivery (Huang et al 2005b).…”