CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues
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Abstract
Although high mammographic density is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high mammographic density share key histologic features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high extracellular matrix (ECM) content. We show that CD36, a transmembrane receptor that coordinately modulates multiple protumorigenic phenotypes, including adipocyte differentiation, angiogenesis, cell–ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high mammographic density and tumor stroma. Using both in vitro and in vivo assays, we show that CD36 repression is necessary and sufficient to recapitulate the above-mentioned phenotypes observed in high mammographic density and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with CD36 expression. Significance: CD36 simultaneously controls adipocyte content and matrix accumulation and is coordinately repressed in multiple cell types within tumor and high mammographic density stroma, suggesting that activation of this stromal program is an early event in tumorigenesis. Levels of CD36 and extent of mammographic density are both modifiable factors that provide potential for intervention. Cancer Discov; 2(9); 826–39. ©2012 AACR. Read the Commentary on this article by DeClerck, p. 772. This article is highlighted in the In This Issue feature, p. 753.
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Altered tissue mechanics are likely to play a role in cancer development and premalignant disease, evidenced by links between mammographic density and breast cancer incidence.
“Altered tissue mechanics are also likely to play a role in cancer development and premalignant disease; this is evidenced by the links between mammographic density and breast cancer incidence84.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [84]
The Introduction (page not provided) reports that high mammographic density is associated with a 4- to 6-fold higher risk of invasive breast cancer and describes differences in stromal composition. The Results section on desmoplasia (page not provided) also finds similar stromal features in high-density, cancer-free tissue and tumor tissue. These passages support the density–risk link, but they do not establish that altered tissue mechanics play a role in cancer development or premalignant disease. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCAF ECM deposition and remodelling depends on RHO and RAB GTPase-mediated control of integrin-mediated adhesions and the actomyosin cytoskeleton and is linked to downregulation of CD36.
“This depends on RHO and RAB GTPase-mediated control of integrin-mediated adhesions and the actomyosin cytoskeleton81–83 and is linked to downregulation of the transmembrane receptor CD36 (also known as platelet glycoprotein 4)84.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [84]
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- Authors
- DeFilippis, R. A., Chang, H., Dumont, N., Rabban, J. T., Chen, Y.-Y., Fontenay, G. V., Berman, H. K., Gauthier, M. L., Zhao, J., Hu, D., Marx, J. J., Tjoe, J. A., Ziv, E., Febbraio, M., Kerlikowske, K., Parvin, B., & Tlsty, T. D.
- Affiliations
- Aurora Health Care (US)
- Corresponding author
- Tlsty, Thea D.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2012-09-01
- Volume
- 2
- Issue
- 9
- Pages
- 826-839
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3457705
- OpenAlex
- W2146971577
- Cited by
- 212
- References
- 52
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 16 · 2023: 15 · 2022: 14 · 2021: 24 · 2020: 36 · 2019: 15 · 2018: 17 · 2017: 7 · 2016: 12 · 2015: 13 · 2014: 8 · 2013: 10 · 2012: 4
- FWCI
- 9.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (U54CA143803, P01CA107584)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Digital Radiography and Breast Imaging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- CD36, breast density, breast cancer, tumor stroma, extracellular matrix, adipogenesis, adipose tissue, carcinogenesis, gene repression, tumor microenvironment, prognostic factors
- MeSH terms
- Animals, Breast Neoplasms, Cell Differentiation, Female, Humans, Mammography, Risk Factors, Signal Transduction, Stromal Cells, Adipocytes, Mice, Knockout, CD36 Antigens, Mice
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