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Kristian Pietras

Kristian Pietras

Research team manager

Kristian Pietras

Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence

Author

  • Steven E Reid
  • Jessica Pantaleo
  • Paulina Bolivar
  • Matteo Bocci
  • Jonas Sjölund
  • Mikkel Morsing
  • Eugenia Cordero
  • Sara Larsson
  • Maria Malmberg
  • Brinton Seashore-Ludlow
  • Kristian Pietras
Show all

Summary, in English

Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the Transforming Growth Factor-β and the Janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced modulation of ER-α activity. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.

Department/s

  • Department of Laboratory Medicine
  • Division of Translational Cancer Research
  • LUCC: Lund University Cancer Centre
  • Food for Health Science Centre, Medicon Village
  • Experimental oncology

Publishing year

2024-02-22

Language

English

Publication/Series

Oncogene

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cancer and Oncology

Status

Epub

Research group

  • Experimental oncology

ISBN/ISSN/Other

  • ISSN: 1476-5594