A growing body of evidence supports a role for progesterone and its derivatives (progestins) (P) in the development of breast cancer. Recent clinical studies have shown that P contributes to a higher breast cancer risk in postmenopausal women receiving combined estrogen + progestin hormone replacement therapy (HRT) compared to women receiving estrogen-alone HRT. On the other hand, pregnancy at an early age reduces the risk of breast cancer and may be directly related to P-induced effects in the breast during pregnancy. Progestins produce their effect in cells by acting through an intracellular progesterone receptor (PR), which exists in two different forms (isoforms), PRA and PRB, and P causes different effects in cells when it interacts with PRA vs. PRB. Normal human mammary cells contain both PRA and PRB in approximately equal amounts. However, in breast tumors the ratio between PRA and PRB is changed, and a high level of PRA in tumors is associated with aggressive tumor behavior and poor prognosis for survival. Several studies have shown that a majority of metastatic tumors express disproportionately high amounts of PRA. We propose to undertake a detailed examination of how P action through PRA or PRB is involved in the development and behavior of mammary cancers using the rat model of mammary cancer development. The rat mammary cancer model is a highly relevant model for this study because the rat and human are remarkably similar with regard to (1) mammary gland structure, site of mammary cancer origin, and pathway of tumor development; (2) hormone dependence of mammary cancers; and (3) the pattern of PR isoform expression and cellular localization; (4) it is known that P treatment enhances mammary cancer development in rats that have not undergone pregnancy; and (5) early pregnancy in rats reduces the occurrence of mammary cancers.

Fifty percent of all primary breast cancers contain PR. Current analysis of PR in tumors does not identify the relative levels of PRA and PRB. To date, we have minimal understanding of how P, PRA, and PRB are involved in the development of breast cancer or in determining tumor behavior and patient survival. It is anticipated that the results of the proposed studies will substantially advance our understanding of how P action through PRA vs. PRB contribute the development and behavior of mammary cancers and how pregnancy confers reduced breast cancer risk. Thus, it is anticipated that in 3-5 years, routine testing of tumors for the relative levels of PRA and PRB could have important prognostic value for predicting tumor behavior and choosing the most effective therapies to improve patient survival. Most importantly, these studies can facilitate the future development of novel therapeutic strategies that target PRA- and/or PRB-specific functions that are associated with poor prognosis. It is also noteworthy that the rat mammary cancer model will be ideally suited for testing novel therapeutic and prevention strategies that target PR function. Ultimately, advancing our understanding of the role of P and PR isoforms in mediating the protective effect of pregnancy may allow us to devise treatments that reproduce the protective effect without a need for pregnancy per se. This would be a major advance toward the prevention and eradication of breast cancer.