From the ranks of mammary progesterone mediators, RANKL takes the spotlight - PubMed (original) (raw)

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From the ranks of mammary progesterone mediators, RANKL takes the spotlight

Rodrigo Fernandez-Valdivia et al. Mol Cell Endocrinol. 2012.

Abstract

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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Figures

Fig. 1

The PRKO mammary phenotype is rescued by RANKL. (A) Using a state-of-theart PRKO bigenic mouse (Mukherjee et al., 2010), transgene-derived RANKL expression is conditionally expressed in PRKO transmitter cells (ER+/PR−) within the luminal epithelium of the mammary gland and only in the presence of the inducer, doxycycline. Location of basal cells and the extracellular matrix (ECM) are also shown in this schematic. (B) An example of the mammary gland of the PRKO bigenic prior to doxycycline administration. As previously reported for the PRKO mouse (Lydon et al., 1995), note the simple ductal structure (black arrow) and absence of alveoli. (C) Typical mammary response in the PRKO bigenic mouse following one-month of doxycycline intake. Note the clear evidence of alveologenesis (black arrowhead) and extensive side-branching. Scale bar in panel B applies to panel C. The data represent a condensed version of those previously reported ((Mukherjee et al., 2010).

Fig. 2

Dual role of RANKL in progesterone/progestin dependent mammary morphogenesis and tumorigenesis. (A) Schematic showing RANKL acting as a paracrine mediator of progesterone-induced mammary side-branching and alveologenesis during pregnancy progression. Increased levels of progesterone bind PR in (PR+) transmitter cells in the luminal epithelium. Ligand-bound PR induces the expression of RANKL which in-turn binds its cell-surface signaling receptor (RANK) on nearby responder cells in the luminal epithelium (LE) and in the basal cell (BC) compartment (see: section 3.5) to elicit mitogenesis (ECM denotes the extracellular matrix). (B) A conceptual depiction of the promotional effect of sustained progestin-induced RANKL signaling on carcinogen (or genetic lesion) induced breast cancer development. In the case of more advanced invasive tumors, RANK+ cancer cells no longer express RANKL due to loss of PR. However, these cancer cells respond in a paracrine manner to an alternative source of RANKL from infiltrating Treg cells; these cells are attracted to the tumor microenvironment by CAF-derived chemokines (Liao et al., 2009). As a consequence of the paracrine signaling between cancer cells and immune cells, cancer cells gain access to the invasion-metastasis cascade which allows for breast cancer cell colonization to distant anatomic sites such as lung and bone. Note: CAF and Treg denote: cancer-associated myofibroblast and regulatory T cell respectively.

Fig. 3

Progesterone-regulates the size and regenerative activity of the MaSC pool through paracrine RANKL signaling. In response to increased levels of progesterone during pregnancy, the PR+ transmitter cell in the luminal epithelium relies on the RANKL paracrine signal to instruct the MaSC population to undergo symmetric cell division. Asymmetric cell division of MaSCs produces lineal-restricted progenitor cells which in-turn generate mature luminal and myoepithelial cells. The rapid increase in mature epithelial cells accounts for most of the increased cellularity observed during the second allometric growth phase of mammary development. Because RANK is expressed in epithelial cells other than the MaSC (Fernandez-Valdivia et al., 2009; Gonzalez-Suarez et al., 2007), RANKL likely influences the mitogenicity of lineal descendants of the MaSC also (dashed line). While this schematic depicts progesterone control of MaSC homeostasis during pregnancy, this signaling paradigm also applies during the progesterone-dominant diestrus stage of the estrous cycle (Joshi et al., 2010).

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From the ranks of mammary progesterone mediators, RANKL takes the spotlight - PubMed (original) (raw)