Abstract NG15: Progesterone-mediated immune evasion in breast cancer

Why are some early neoplastic lesions identified through immunosurveillance and subsequently destroyed, whereas other tumors evade this clearance step and progress to clinically-relevant tumors? The cancer immunoediting hypothesis highlights that the innate and adaptive immune responses work together to “flag” early neoplastic lesions for immune-mediated elimination. An early mediator of this “elimination” process is activation of type I interferon signaling. Thus, suppression of type I interferon signaling may help developing tumors evade the critical early steps of immune recognition and clearance. As such, female STAT1 knockout mice, lacking the key upstream activator of type I interferon signaling, develop mammary gland adenocarcinomas. Preliminary data from our lab suggest that progesterone, working through the progesterone receptor (PR), may be a key player in tumor immune evasion. The contribution of the ovarian steroid hormone, progesterone, to the development and progression of breast cancer has become increasingly evident, especially in light of recent clinical trial data linking the use of hormonal replacement therapy with breast cancer risk. These highly publicized data showed that women whose hormone replacement therapy (HRT) regimens included synthetic progesterone had a higher relative risk of developing invasive breast cancer. These data underscore the importance of understanding how hormones, particularly progesterone, affect breast cancer initiation and growth. Upon diagnosis, nearly 70% of breast cancers express PR and the estrogen receptor (ER). This is in sharp contrast to what is seen in the normal mammary gland, where only 7-10% of luminal epithelial cells express ER and PR. ER action in breast cancer has been well studied and as a result, ER has proven to be an excellent target for current endocrine-based therapies. However, despite convincing clinical evidence from the aforementioned trials, the role of PR in breast cancer has been largely understudied. Importantly, progesterone is emerging as a potent mitogen in the breast and a significant contributor to breast cancer progression. Despite maintaining receptor (ER/PR) expression, many breast cancer patients eventually progress to hormone-independence, failing current (largely ER/estrogen based) endocrine therapies. Therefore, ER-independent functions of PR are of great clinical interest. PR is a steroid-activated nuclear transcription factor known to regulate context-dependent gen