Cited by 212Digital Radiography and Breast ImagingCancer, Lipids, and MetabolismBreast Cancer Treatment Studies

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CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues

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DeFilippis, Rosa Anna, Chang, Hang, Dumont, Nancy, Rabban, Joseph T., Chen, Yunn-Yi, Fontenay, Gerald V., Berman, Hal K., Gauthier, Mona L., Zhao, Jianxin, Hu, Donglei, Marx, James J., Tjoe, Judy A., Ziv, Elad, Febbraio, Maria, Kerlikowske, Karla, Parvin, Bahram, Tlsty, Thea D.·2012·Cancer Discovery

DOI 10.1158/2159-8290.cd-12-0107PMC PMC3457705

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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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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: Chang, Hang
Dumont, Nancy
Rabban, Joseph T.
Chen, Yunn-Yi
Berman, Hal K.
Hu, Donglei
Ziv, Elad
Febbraio, Maria
Kerlikowske, Karla
Parvin, Bahram
Tlsty, Thea D.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2012-09-01
Volume: 2
Issue: 9
Pages: 826-839
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-12-0107
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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CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues

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