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Steroid hormone receptors and coregulators in endocrine‐resistant and estrogen‐independent breast cancer cells
Author(s) -
Sarvilinnna,
Eronen Heli,
Miettinen Susanna,
Vien Annika,
Ylikomi Timo
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21431
Subject(s) - endocrinology , estrogen receptor , medicine , estrogen , nuclear receptor , fulvestrant , estrogen receptor beta , tamoxifen , cancer research , biology , thyroid hormone receptor , estrogen receptor alpha , hormone , breast cancer , cancer , transcription factor , biochemistry , gene
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 anti‐estrogen‐resistant cells. Estrogen caused PR and ERβ 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 ERα 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 (N‐CoR) 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.