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Progesterone Receptors and Hormonal Prevention of Breast Cancer
Background: Early pregnancy in rodents and humans or three week treatment of rodents with low doses of estrogen plus progesterone (E+P) produces a mammary gland phenotype that is refractory to subsequent chemical induced carcinogenesis. Neither E nor P alone will induce this response nor can it be induced by the dopamine antagonist perphenazine, a compound that elicits sustained high levels of serum prolactin and induces differentiation of mammary epithelial cells. The cellular and molecular mechanisms that underlie steroid hormone- and parity-induced refractoriness to carcinogenesis are largely unresolved. The requirement for P in inducing the refractory phenotype underscores a critical role for progesterone receptors (PRs) in addition to estrogen receptors in steroid inhibition of breast tumor development. The effects of P are mediated by two distinct receptor isoforms, PR-A and PR-B. By selective abrogation of expression of individual PR isoforms in mice, we recently demonstrated that these receptors can mediate distinct tissue selective responses to P in the female reproductive tract and mammary gland.
Hypothesis/Objective: Based on the differential activities of PR-A and PR-B in mediating normal mammary gland morphogenesis, we hypothesize that these isoforms may have distinct activities with regard to induction of a P dependent refractory phenotype to carcinogenesis. However, the contributions of the PR-A and PR-B isoforms to this response have not been addressed and will be the focus of this proposal.
Specific Aims: 1) To examine the contribution of the individual PR isoforms to E+P dependent tumor protection in mice and 2) To examine the PR isoform selective signaling pathways that contribute to the refractory phenotype induced by E+P
Study Design: To address Aim 1, we will determine whether early treatment with E+P induces a refractory phenotype to carcinogenesis in mice lacking PR-A or PR-B. To address aim 2, we will examine PR isofrom selectivity of regulation of signaling pathways that contribute to the refractory phenotype by analysis of the expression of recently identified molecular markers associated with tumor resistance in mice lacking PR-A or PR-B.
Potential Outcomes and Benefits of Research: Recent advances in identification of increased breast cancer risk factors in women have highlighted the need for urgent development of chemopreventive strategies for protection against development of the disease. The robust and reproducible protection against tumorigenesis that is achieved by early manipulation of endocrine status represents a potentially powerful approach to reduce breast cancer risk in later life. Understanding the molecular mechanisms that underlie this response is essential in facilitating the design of novel chemoprevention strategies that mimic the developmental stage specific chemopreventative effects of endocrine hormones. Given the central role of P in this response, the novel mouse models we have generated will play a critical role in dissecting the molecular genetic mechanisms that underlie steroid hormone dependent tumor prevention and will facilitate the rational design of novel chemotherapeutic agents that mimic these endocrine events.
Despite significant improvements in detection methods to identify women with increased risk for development of breast cancer, there remains an urgent need to accelerate development of approaches to prevention of disease development. While early full term pregnancy in humans provides significant protection against development of breast cancer in later life, the molecular mechanisms by which modulation of endocrine status in early life can alter breast cancer risk are under explored and poorly understood.
The general mechanisms that underlie both mammary gland development and tumorigenesis are conserved between rodents and humans. The mouse model system, because it is amenable to genetic manipulation, thus provides a powerful tool to elucidate the molecular genetic pathways that control these events. The protective effects of early full term pregnancy in humans can be reproduced by early pregnancy in rodents or by a three week treatment of young animals with low doses of estrogen and progesterone (E+P). The tumor protective effect afforded by early treatment with E+P is dramatic resulting in almost complete protection against a tumorigenic response to subsequent carcinogen challenge and P is essential for the response. The robust nature of this protection and its reproducibility in rodents provides an excellent opportunity to explore the mechanisms by which early hormonal exposure induces persistent changes in mammary epithelial cell fate that render these cells less susceptible to carcinogen insult. Elucidation of these mechanisms should facilitate the design of novel therapeutic agents that can mimic endocrine modulation of cancer risk as well as provide essential molecular markers to monitor changes in tumor susceptibility of mammary epithelial cells.