Steroid hormone receptors and coregulators in endocrine‐resistant and estrogen‐independent breast cancer cells

Abstract

Resistance to hormonal therapy is often a problem in the treatment of breast cancer patients. It has been suggested that resistance could be explained by altered nuclear hormone receptor or coregulator levels or inappropriately increased agonist activity of selective estrogen receptor modulator (SERM). To test these hypotheses, we have established novel MCF-7 cell line-derived in vitro models of anti-estrogen-and progestin-resistant and estrogen-independent breast cancer by long-term culture in the presence of toremifene and medroxyprogesterone acetate (MPA) and in the absence of estradiol, respectively. Using cell growth and multiprobe ribonuclease protection assays, the expression of 5 nuclear hormone receptors and 9 coregulators as well as the alterations in the cell proliferation and target gene transcription in response to hormonal treatments were studied. Progesterone receptor (PR) expression was decreased and silencing mediator for retinoid acid and thyroid hormone receptors (SMRT) and amplified in breast cancer-1 (AIB1) expression increased in antiestrogen-resistant cells. Estrogen caused PR and ERb upregulation in all cell lines, but we did not observe increased agonist activity of anti-estrogen measured by regulation of these estrogen target genes. Basal ERa levels and estrogenic growth response were decreased and p300/CBP-associated factor (pCAF) and AIB1 upregulated by estrogen in progestin-resistant cells, but coregulator levels were unchanged. Estrogen-independent cells were still estrogen-responsive and PR, nuclear receptor corepressor (NCoR) and SMRT expression was increased whereas steroid receptor coactivator-1 (SRC-1a) and CBP-related protein p300 (p300) expression decreased. Their growth was inhibited by toremifene, but estradiol was able to abrogate this effect, which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy. ' 2005 Wiley-Liss, Inc.

Changes in expression of steroid receptors, their downstream target genes and their associated co-regulators during the sequential acquisition of tamoxifen resistance in vitro

“…A reduction in PR was consistent with the development of TAMr. These general observations are consistent with other published TAMr models (27)(28)(29)(30)(31)(32). Table III.…”

“…Some examples of genes up-and down-regulated in MCF-7 MMU1 cells relative to wtMCF-7 cells following microarray analysis. ------------------------------------------------ ERα expression exceeded that of ERß in accord with other studies (32)(33)(34)(35)(36). This has also proven to be the case in a xenograft model of anti-estrogen resistance and in clinical breast cancer (37,38).…”

“…AIB-1 expression correlated with poorer prognosis in breast cancer and reduced response to hormonal therapy (15). Elevated levels of AIB-1 have been reported in other breast cancer cell studies (32,33,44,45). Elevated levels in our in vitro TAMr model strengthen the involvement of AIB-1 in breast carcinogenesis and its further elevation in TAMr suggests it may be contributory to this phenomenon.…”

“…Fleming et al (47) confirmed the preferential recruitment of this repressor to the ER in the presence of 4-HT. More recently basal expression of SMRT was significantly increased in toremifene-resistant cells (32). Silencing of both NCoR-1 and SMRT expression by siRNA resulted in TAM-stimulated proliferation in MCF-7 cells (57), supporting a role for these co-repressors in the TAMr phenotype.…”

Molecular aspects of bovine cystic ovarian disease pathogenesis

“…4; Delage-Mourroux et al 2000). Under these circumstances, some hormone-dependent organs or tumors exhibit over-expression of the NCOA family members that would be directly involved in the increase in cell proliferation and differentiation, indicating their important physiological role (Sarvilinna et al 2006, Mukherjee et al 2007.…”