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CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues
Open accessPublished version of a preprint
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 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]
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“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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Cites
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Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
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Stromal gene expression predicts clinical outcome in breast cancer
Finak, G., Bertos, N., Pepin, F., Sadekova, S., Souleimanova, M., Zhao, H., Chen, H., Ömeroğlu, G., Meterissian, S. H., Ömeroğlu, A., et al. (2008) · Nature Medicine · doi:10.1038/nm1764 · Cited by 1,707
Carcinoma-associated fibroblasts stimulate tumor progression of initiated human epithelium
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Self-citationCollagen density promotes mammary tumor initiation and progression
Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Knittel, J. G., Yan, L., Rueden, C., White, J. G., & Keely, P. J. (2008) · BMC Medicine · doi:10.1186/1741-7015-6-11 · Cited by 1,394
Macrophage polarization in tumour progression
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Self-citationCellular Fatty Acid Metabolism and Cancer
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Metadata
- 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 › Radiology, Nuclear Medicine and Imaging › 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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