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Cancer Res. 2014 Sep 15;74(18):5032-5044. doi: 10.1158/0008-5472.CAN-13-3390. Epub 2014 Aug 29.

Stress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density.

Author information

1
Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.
2
Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA.
3
Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
4
Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
5
Departments of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, 94143, USA.
#
Contributed equally

Abstract

Telomere malfunction and other types of DNA damage induce an activin A-dependent stress response in mortal nontumorigenic human mammary epithelial cells that subsequently induces desmoplastic-like phenotypes in neighboring fibroblasts. Some characteristics of this fibroblast/stromal response, such as reduced adipocytes and increased extracellular matrix content, are observed not only in tumor tissues but also in disease-free breast tissues at high risk for developing cancer, especially high mammographic density tissues. We found that these phenotypes are induced by repression of the fatty acid translocase CD36, which is seen in desmoplastic and disease-free high mammographic density tissues. In this study, we show that epithelial cells from high mammographic density tissues have more DNA damage signaling, shorter telomeres, increased activin A secretion and an altered DNA damage response compared with epithelial cells from low mammographic density tissues. Strikingly, both telomere malfunction and activin A expression in epithelial cells can repress CD36 expression in adjacent fibroblasts. These results provide new insights into how high mammographic density arises and why it is associated with breast cancer risk, with implications for the definition of novel invention targets (e.g., activin A and CD36) to prevent breast cancer.

PMID:
25172842
PMCID:
PMC4335659
DOI:
10.1158/0008-5472.CAN-13-3390
[Indexed for MEDLINE]
Free PMC Article

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