Breast cancer resistance
protein (BCRP)/ABCG2 mediates concurrent resistance to chemotherapeutic agents, such as
7-ethyl-10-hydroxycamptothecin (SN-38),
mitoxantrone, and
topotecan, by pumping them out of cells. We previously reported that BCRP transports sulfated
estrogens. In the present study, we show that at physiologic levels,
estrogens markedly decrease endogenous BCRP expression in the
estrogen-responsive and
estrogen receptor alpha (
ERalpha)-positive human
breast cancer MCF-7 cells, but not in
estrogen-nonresponsive human
cancer cells.
17 beta-Estradiol (E(2)) also significantly reduces exogenous BCRP expression, driven by a constitutive promoter, in BCRP-transduced
estrogen-responsive and
ERalpha-positive MCF-7 (MCF-7/BCRP) and T-47D cells, but not in BCRP-transduced
estrogen-nonresponsive MDA-MB-231 and SKOV-3 cells. E(2) potentiates the cytotoxicity of
SN-38, but not
vincristine, in MCF-7/BCRP cells significantly, and increases cellular
topotecan uptake in MCF-7 and MCF-7/BCRP cells.
Antiestrogen tamoxifen partially reverses E(2)-mediated BCRP down-regulation in MCF-7 and MCF-7/BCRP cells and treatment of MCF-7/BCRP cells with an
ERalpha small interfering RNA abolished E(2)-mediated BCRP down-regulation, suggesting that interaction of E(2) and
ERalpha is necessary for BCRP down-regulation. E(2) does not affect endogenous BCRP
mRNA levels in MCF-7 cells or exogenous BCRP
mRNA levels in MCF-7/BCRP cells. The results from pulse-chase labeling experiments with MCF-7/BCRP cells suggest that decreased protein biosynthesis and maturation, but not alterations in
protein turnover, might underlie E(2)-mediated BCRP down-regulation. These data indicate that
estrogen down-regulates BCRP expression by novel posttranscriptional mechanisms. This is the first report of small molecules that can affect BCRP
protein expression in cells and may therefore assist in establishing new strategies for regulating BCRP expression.