Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling
Menée à l'aide de modèles murins de cancer du sein, cette étude met en évidence des mécanismes par lesquels, dans le micro-environnement tumoral, les fibroblastes associés au cancer déterminent le statut "basal-like" d'une tumeur, puis montre que ce statut est réversible en HR+ par une intervention génétique ou pharmacologique
Breast tumors of the basal-like, hormone receptor–negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support 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 paracrine crosstalk 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 of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal-like subtype is under microenvironmental control and is therapeutically actionable.
Nature Medicine 2018