Several
estrogen mimics (xenoestrogens) inappropriately activate the
estrogen receptor (ER) in the absence of endogenous
ligand. Given the importance of the ER in
breast cancer growth and regulation, delineating the impact of these agents under conditions related to
tumor treatment is of significant importance. We examined the effect of two prevalent xenoestrogens (
bisphenol A and
coumestrol) on ER activation and ER-dependent mitogenesis in
breast cancer cells. We show that the ability of these agents to induce mitogenesis was restricted to conditions of
estrogen depletion, and that these agents failed to cooperate with
estradiol to induce MCF-7
breast cancer cell growth. These observations are consistent with the impact of each agent specifically on exogenous ER activation as monitored in HeLa cells, wherein the xenoestrogens activated the receptor in the absence of
estradiol but failed to cooperate with
estrogen.
Tamoxifen blocked
bisphenol A and
coumestrol-mediated ER activation, indicating that exposure to these agents is unlikely to disrupt such therapeutic intervention. The response of
tumor-derived ER alleles to these xenoestrogens was also examined. Although the xenoestrogens failed to alter ER-Y537S function, the ER-D351Y mutant demonstrated an enhanced response to
bisphenol A. Moreover,
tamoxifen enhanced the agonistic effects of xenoestrogens on ER-D351Y. Lastly, we examined the impact of ER co-activator overexpression on xenoestrogen response.
Bisphenol A and
coumestrol exhibited differential responses to co-activators with regard to ER activation. However, when using mitogenesis as an endpoint, these co-activators were insufficient to provide a significant growth advantage. Combined, these data demonstrate that
bisphenol A and
coumestrol can impact ER activity and ER-dependent proliferation in
breast cancer cells, but the influence of these agents is restricted to conditions of
estrogen depletion, selective mutation of the ER, and expression of specific co-activators.