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

• Published in: Nature medicine Vol. 24; no. 4; pp. 463 - 473
• Main Authors: Roswall, Pernilla, Bocci, Matteo, Bartoschek, Michael, Li, Hong, Kristiansen, Glen, Jansson, Sara, Lehn, Sophie, Sjölund, Jonas, Reid, Steven, Larsson, Christer, Eriksson, Pontus, Anderberg, Charlotte, Cortez, Eliane, Saal, Lao H, Orsmark-Pietras, Christina, Cordero, Eugenia, Haller, Bengt Kristian, Häkkinen, Jari, Burvenich, Ingrid J G, Lim, Elgene, Orimo, Akira, Höglund, Mattias, Rydén, Lisa, Moch, Holger, Scott, Andrew M, Eriksson, Ulf, Pietras, Kristian
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2018; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/106; 13/51; 13/95; 14/63; 38/61; 38/90; 631/67/1347; 631/67/327; 64/110; 64/60; Animal models; Animals; Biomarkers, Tumor - metabolism; Biomedicine; Breast cancer; Breast Neoplasms - blood supply; Breast Neoplasms - pathology; Cancer; Cancer and Oncology; Cancer och onkologi; Cancer Research; Cancer-Associated Fibroblasts - metabolism; Care and treatment; Cell Line, Tumor; Cell Proliferation; Cellular signal transduction; Clinical Medicine; Coevolution; Crosstalk; Development and progression; Endocrine therapy; Epithelial Cells - metabolism; Epithelium; Estrogen Receptor alpha - metabolism; Female; Fibroblasts; Fibrosis; Genetic aspects; Growth factors; Health aspects; Humans; Infectious Diseases; Klinisk medicin; Lymphokines - deficiency; Lymphokines - metabolism; Mammary gland; Medical and Health Sciences; Medicin och hälsovetenskap; Metabolic Diseases; Mice, Inbred C57BL; Middle Aged; Molecular Medicine; Neovascularization, Pathologic - pathology; Neurosciences; Paracrine Communication; Paracrine signalling; Pharmacology; Platelet-derived growth factor; Platelet-Derived Growth Factor - deficiency; Platelet-Derived Growth Factor - metabolism; Prognosis; Proportional Hazards Models; Receptors; Sensitivity enhancement; Signal Transduction; Stroma; Stromal Cells - pathology; Survival Analysis; Treatment Outcome; Tumor Microenvironment; Tumors
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.4494

Paracrine signaling networks in the breast cancer microenvironment uncover determinants of hormone receptor status and offer opportunities for therapeutic intervention. 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.