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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 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.

Type Journal
ISBN 1546-170X (Electronic) 1078-8956 (Linking)
Authors Roswall, P.; Bocci, M.; Bartoschek, M.; Li, H.; Kristiansen, G.; Jansson, S.; Lehn, S.; Sjolund, J.; Reid, S.; Larsson, C.; Eriksson, P.; Anderberg, C.; Cortez, E.; Saal, L. H.; Orsmark-Pietras, C.; Cordero, E.; Haller, B. K.; Hakkinen, J.; Burvenich, I. J. G.; Lim, E.; Orimo, A.; Hoglund, M.; Ryden, L.; Moch, H.; Scott, A. M.; Eriksson, U.; Pietras, K.
Responsible Garvan Author Prof Elgene Lim
Published Date 2018-05-01
Published Volume 24
Published Issue 4
Published Pages 463-473
Status Published in-print
DOI 10.1038/nm.4494
URL link to publisher's version