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

Reid, Steven E LU ; Pantaleo, Jessica LU ; Bolivar, Paulina LU ; Bocci, Matteo LU orcid ; Sjölund, Jonas LU ; Morsing, Mikkel ; Cordero, Eugenia ; Larsson, Sara LU ; Malmberg, Maria LU and Seashore-Ludlow, Brinton , et al. (2024) In Oncogene
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Oncogene
pages
14 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85185666632
  • pmid:38388711
ISSN
1476-5594
DOI
10.1038/s41388-024-02973-x
language
English
LU publication?
yes
additional info
© 2024. The Author(s).
id
0ebc9f81-7160-4d33-9ef7-d12ea6f75a41
date added to LUP
2024-02-28 10:11:55
date last changed
2024-06-23 06:58:50
@article{0ebc9f81-7160-4d33-9ef7-d12ea6f75a41,
  abstract     = {{<p>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.</p>}},
  author       = {{Reid, Steven E and Pantaleo, Jessica and Bolivar, Paulina and Bocci, Matteo and Sjölund, Jonas and Morsing, Mikkel and Cordero, Eugenia and Larsson, Sara and Malmberg, Maria and Seashore-Ludlow, Brinton and Pietras, Kristian}},
  issn         = {{1476-5594}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Oncogene}},
  title        = {{Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence}},
  url          = {{http://dx.doi.org/10.1038/s41388-024-02973-x}},
  doi          = {{10.1038/s41388-024-02973-x}},
  year         = {{2024}},
}