Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling

Breast tumors of the basal-like, hormone receptor-negative, subtype remain an unmet clinical challenge, as patients exhibit a high rate of recurrence and poor survival. Co-evolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to endorse most, if not all, hallmarks of cancer progression. Here, we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified a paracrine cross-talk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention with PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that conferred sensitivity to endocrine therapy in previously impervious tumors. We conclude that specification of the basal-like subtype of breast cancer is under microenvironmental control and therapeutically actionable in order to achieve sensitivity to endocrine therapy.