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

journal contribution
posted on 15.10.2021, 00:03 authored by Pernilla Roswall, Matteo Bocci, Michael Bartoschek, Hong Li, Glen Kristiansen, Sara Jansson, Sophie Lehn, Jonas Sjölund, Steven Reid, Christer Larsson, Pontus Eriksson, Charlotte Anderberg, Eliane Cortez, Lao H Saal, Christina Orsmark-Pietras, Eugenia Cordero, Bengt Kristian Haller, Jari Häkkinen, Ingrid JG Burvenich, Elgene Lim, Akira Orimo, Mattias Höglund, Lisa Rydén, Holger Moch, Andrew ScottAndrew Scott, Ulf Eriksson, Kristian Pietras
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.

Funding

We gratefully acknowledge expert help with pathology assessments from the late D. Grabau and provision of the Tam2Y cohort by M. Ferno. 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 Goran & 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.

History

Publication Date

01/04/2018

Journal

Nature Medicine

Volume

24

Issue

4

Pagination

11p. (p. 463-473)

Publisher

Springer Nature

ISSN

1078-8956

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