Epithelial and non-epithelial <i>Ptch1</i> play opposing roles to regulate proliferation and morphogenesis of the mouse mammary gland

Abstract

Patched 1 (<i>Ptch1</i>) has epithelial, stromal and systemic roles in murine mammary gland organogenesis, yet specific functions remain undefined. <i>Cre</i>-recombinase-mediated <i>Ptch1</i> ablation in mammary epithelium increased proliferation and branching, but did not phenocopy transgenic expression of activated smoothened (<i>SmoM2</i>). The epithelium showed no evidence of canonical hedgehog signaling, and hyperproliferation was not blocked by smoothened (SMO) inhibition, suggesting a non-canonical function of PTCH1. Consistent with this possibility, nuclear localization of cyclin B1 was increased. In non-epithelial cells, heterozygous <i>Fsp-Cre-</i>mediated <i>Ptch1</i> ablation increased proliferation and branching, with dysplastic terminal end buds (TEB) and ducts. By contrast, homozygous <i>Ptch1</i> ablation decreased proliferation and branching, producing stunted ducts filled with luminal cells showing altered ovarian hormone receptor expression. Whole-gland transplantation into wild-type hosts or estrogen/progesterone treatment rescued outgrowth and hormone receptor expression, but not the histological changes. Bone marrow transplantation failed to rescue outgrowth. Ducts of <i>Fsp-Cre;Ptch1^fl/fl</i> mice were similar to <i>Fsp-Cre;SmoM2</i> ducts, but <i>Fsp-Cre;SmoM2</i> outgrowths were not stunted, suggesting that the histology might be mediated by <i>Smo</i> in the local stroma, with systemic <i>Ptch1</i> required for ductal outgrowth and proper hormone receptor expression in the mammary epithelium.