Whether during the diestrus phase of the estrous cycle or with pregnancy onset, the mitogenic effects of progesterone are well-established in the murine mammary epithelium. Importantly, progesterone-induced mitogenicity is critical for mammary tumor promotion, providing one explanation for the increase in breast cancer-risk observed with prolonged progestin-based hormone therapy. At the cellular level, progesterone projects its mitogenic influence through an evolutionary conserved paracrine mechanism of action. In this regard, recent studies provide compelling support for receptor activator of NF-kB ligand (RANKL) as a key paracrine mediator of the progesterone mitogenic signal. Induction of RANKL is sufficient to elicit mammary ductal side-branching and alveologenesis, the very morphogenetic responses elicited by progesterone during pregnancy and at diestrus. Significantly, the proliferative and pro-survival signals triggered by RANKL are also required for progestin-promotion of mammary tumorigenesis, underscoring a dual role for RANKL in progesterone-dependent mammary morphogenesis and tumorigenesis. Recently, RANKL has been shown to be critical for progesterone-induced expansion of the mammary stem cell population (and its lineal descendents), thereby advancing our conceptual understanding not only of RANKL's involvement in normal mammary morphogenesis but also in breast cancer risk associated with sustained hormone exposure. Finally, these studies together suggest that chemotherapeutic intervention of RANKL signaling represents a feasible approach for the effective prevention and/or treatment of hormone-responsive breast cancers.
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