Abstract
IntroductionEstrogen and androgen signalling pathways exert opposing influences on the proliferation of mammary epithelial and hormone-dependent breast cancer cells. We previously reported that plasma concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), the main metabolite of the insecticide DDT (1,1,1-trichloro-2,2-bis [p-chlorophenyl]ethane) and a potent androgen antagonist, were associated with tumor aggressiveness in women diagnosed with breast cancer. We sought to examine the biological plausibility of this association by testing the effect of p,p'-DDE on the proliferation of CAMA-1 cells, a human breast cancer cell line that expresses the estrogen receptor alpha (ERα) and the androgen receptor (AR), in the presence of physiological concentrations of estrogens and androgens in the cell culture medium.MethodsThe proliferation of CAMA-1 cells was determined in 96-well plates following a 9-day treatment with p,p'-DDE alone (0.1 to 10 μM) or in combination with 17β-estradiol (E2) (100 pM) and dihydrotestosterone (DHT) (100, 500, or 1,000 pM). We also assessed p,p'-DDE-induced modifications in cell cycle entry and the expression of the sex-steroid-dependent genes ESR1, AR, CCND1, and TFF1 (pS2) (mRNA and/or protein).ResultsWe found that treatment with p,p'-DDE induced a dose-response increase in the proliferation of CAMA-1 cells when cultivated in the presence of physiological concentrations of estrogens and androgens, but not in the absence of sex steroids in the cell culture medium. A similar effect of p,p'-DDE was noted on the proliferation of MCF7-AR1 cells, an estrogen-responsive cell line that was genetically engineered to overexpress the AR. DHT added together with E2 to the cell culture medium decreased the recruitment of CAMA-1 cells in the S phase and the expression of ESR1 and CCND1 by comparison with cells treated with E2 alone. These androgen-mediated effects were blocked with similar efficacy by p,p'-DDE and the potent antiandrogen hydroxyflutamide.ConclusionOur results suggest that p,p'-DDE could increase breast cancer progression by opposing the androgen signalling pathway that inhibits growth in hormone-responsive breast cancer cells. The potential role of environmental antiandrogens in breast carcinogenesis deserves further investigation.
Highlights
Estrogen and androgen signalling pathways exert opposing influences on the proliferation of mammary epithelial and hormone-dependent breast cancer cells
We found that treatment with p,p'-DDE induced a doseresponse increase in the proliferation of CAMA-1 cells when cultivated in the presence of physiological concentrations of estrogens and androgens, but not in the absence of sex steroids in the cell culture medium
DHT added together with E2 to the cell culture medium decreased the recruitment of CAMA-1 cells in the S phase and the expression of ESR1 and CCND1 by comparison with cells treated with E2 alone
Summary
Estrogen and androgen signalling pathways exert opposing influences on the proliferation of mammary epithelial and hormone-dependent breast cancer cells. We previously reported that plasma concentrations of 1,1-dichloro-2,2-bis(pchlorophenyl)ethylene (p,p'-DDE), the main metabolite of the insecticide DDT (1,1,1-trichloro-2,2-bis [p-chlorophenyl]ethane) and a potent androgen antagonist, were associated with tumor aggressiveness in women diagnosed with breast cancer. We sought to examine the biological plausibility of this association by testing the effect of p,p'-DDE on the proliferation of CAMA-1 cells, a human breast cancer cell line that expresses the estrogen receptor alpha (ERα) and the androgen receptor (AR), in the presence of physiological concentrations of estrogens and androgens in the cell culture medium. In vitro studies revealed that the loss of normal cell cycle control in hormone-dependent breast cancer cells can result from treatment with xenoestrogens as indicated by increased cell proliferation and modulation of estrogen-sensitive molecular parameters [8,9]. The sum of evidence from several epidemiological studies that investigated the relationship between breast cancer and exposure to persistent organochlorines, some of them with known estrogenic properties, does not support a link between any of these compounds and breast cancer risk [10,11]
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