Intersections between progesterone receptor and beta-catenin signaling in mammary development and breast cancer

Progesterone receptor (PR) and beta-catenin signaling play critical roles in mammary development during pregnancy. Loss-of-function experiments have demonstrated that these proteins play a role in alveologenesis. However, connections between PR and beta-catenin signaling have not yet been examined. This study demonstrates that activated beta-catenin specifically rescues alveologenesis in progesterone receptor null (PR-/-) mice during pregnancy. Moreover, beta-catenin-responsive cells switch on an alveolar differentiation program that is restrained by PR signaling and is indistinguishable from pregnancy-induced alveolar differentiation. This study also demonstrates that the virgin gland contains two distinct subsets of mammary cells that respond to activated beta-catenin. One subset is intrinsically beta-catenin-responsive and is located at ductal tips. In contrast, the second subset relies on PR signaling to confer beta-catenin responsiveness, and is distributed along the lateral ductal borders. Thus, the PR increases the susceptibility of the gland to beta-catenin-induced hyperplasia. However, PR reduces the proportion of hyperplastic lesions progressing to tumors and increases the latency of beta-catenin-induced tumors. As beta-catenin induces hormone receptor negative tumors, PR-mediated restraint is likely to act via paracrine factors or by inducing cell fate changes.