CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues

TitleCD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues
Publication TypeJournal Article
Year of Publication2012
AuthorsDeFilippis RAnna, Chang H, Dumont N, Rabban JT, Chen Y-Y, Fontenay GV, Berman HK, Gauthier ML, Zhao J, Hu D, Marx JJ, Tjoe JA, Ziv E, Febbraio M, Kerlikowske K, Parvin B, Tlsty TD
JournalCancer Discov
Volume2
Issue9
Pagination826-39
Date Published2012 Sep
ISSN2159-8290
KeywordsAdipocytes, Animals, Antigens, CD36, Breast Neoplasms, Cell Differentiation, Female, Humans, Mammography, Mice, Mice, Knockout, Risk Factors, Signal Transduction, Stromal Cells
Abstract

UNLABELLED: 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.

DOI10.1158/2159-8290.CD-12-0107
Alternate JournalCancer Discov
PubMed ID22777768
PubMed Central IDPMC3457705
Grant ListP01 CA107584 / CA / NCI NIH HHS / United States
P01 CA107584 / CA / NCI NIH HHS / United States
U54 CA143803 / CA / NCI NIH HHS / United States
U54 CA143803 / CA / NCI NIH HHS / United States