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

Abstract

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.

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Figure 1: Epithelial expression of PDGF-CC is associated with a poor outcome in patients with breast carcinoma.
Figure 2: Expression of PDGF-CC in breast carcinomas is associated with the hormone receptor–negative, basal-like molecular subtype.
Figure 3: CAF-derived factors whose expression is induced by PDGF-CC reduce the sensitivity of breast tumor cells to endocrine therapy.
Figure 4: Genetic or pharmacological targeting of PDGF-CC induces expression of ERα and sensitizes tumors to endocrine therapy.

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Acknowledgements

We gratefully acknowledge expert help with pathology assessments from the late D. Grabau and provision of the Tam2Y cohort by M. Fernö. Further, we would like to thank D. Cao, M. O'Brien and C. Murone for their technical support and P.-O. Bendahl for statistical assistance. K.P. is the Göran & Birgitta Grosskopf Professor at Lund University. The research presented herein was supported by grants from the following agencies to K.P.: a Consolidator Grant from the European Research Council (the TUMORGAN project, grant 309322), the Swedish Research Council, the Swedish Cancer Society, the STARGET consortium (a Swedish Research Council Linnaeus network), BioCARE and Lund University. U.E. acknowledges funding support from the Swedish Research Council, the Swedish Cancer Society, Karolinska Institutet and Ludwig Institute for Cancer Research. A.M.S. acknowledges funding support from National Health and Medical Research Council (NHMRC) Fellowship 1084178 and Grant 10927888 and the Operational Infrastructure Support Program provided by the Victorian Government, Australia.

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P.R. generated and analyzed data and conceived the study. M. Bocci, M. Bartoschek, H.L., G.K., S.J., S.L., J.S., C.L., P.E., S.R., C.A., E. Cortez, L.H.S., C.O.-P., B.K.H. and J.H. generated and analyzed data. E. Cordero, I.J.G.B. and E.L. generated data. A.O. provided exclusive reagents. M.H. analyzed data. L.R., H.M. and A.M.S. analyzed data and provided exclusive reagents. U.E. analyzed data, provided exclusive reagents and conceived the study. K.P. generated and analyzed data, conceived the study, managed the study and wrote the manuscript.

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Correspondence to Kristian Pietras.

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Competing interests

K.P., U.E. and P.R. are named inventors on Patent Cooperation Treaty (PCT) application no. PCT/EP2016/077295, which is related to the findings of the current study. K.P., U.E. and A.M.S. are shareholders of Paracrine Therapeutics, which develops inhibitory agents to PDGF-CC.

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Roswall, P., Bocci, M., Bartoschek, M. et al. Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling. Nat Med 24, 463–473 (2018). https://doi.org/10.1038/nm.4494

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