The role of the AH receptor in estrogen-sensitive breast cancer

Occupational And Environmental Health

My research is focused on the molecular mechanisms mediating the interaction between the aryl hydrocarbon (AHR) and estrogen receptors  (ER), and understanding how these interactions affect the development of breast cancer. The objectives of this proposal are to define the role of AHR in ER-function relevant to the development and treatment of cancer. Cancers of the breast are linked to an estrogen-rich milieu and aberrant cell growth regulated by ER. There will be over 2700 new cases of breast cancer in British Columbia and the Yukon this year alone. Proteins associated with the development of these cancers represent therapeutic targets. Activators of AHR constitute a variety of environmental pollutants, most of which are capable of inhibiting estrogen sensitive tumour growth. My lab has demonstrated that a significant component of AHR-mediated repression of estrogen signaling is through the physical tethering of AHR to ER as ER regulates gene expression. The hypothesis of this proposal is that manipulation of AHR tethering to ER may ameliorate the carcinogenic effects of aberrant ER activation. I propose to identify proteins involved in this process and the cohort of estrogen regulated genes whose expression is affected in response to activators of AHR.  These targets likely represent the effectors of estrogen-sensitive tumour cell growth, and may represent novel therapeutic targets in the treatment these cancers. Several compounds that inhibit mammary tumor growth in rodents, bind AHR but are poor activators of AHR inducible gene transcription. We will develop a screen for non-classical activators of the AHR, as these may prove to have therapeutic value in the treatment of many cancers as they may induce AHR-dependent repression of ER-regulated transcription, yet not elicit the adverse effects associated with AHR target gene activation, or those associated with long-term tamoxifen therapy.