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

TitleStress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density
Publication TypeJournal Article
Year of Publication2014
AuthorsDeFilippis RAnna, Fordyce C, Patten K, Chang H, Zhao J, Fontenay GV, Kerlikowske K, Parvin B, Tlsty TD
JournalCancer Res
Volume74
Issue18
Pagination5032-44
Date Published2014 Sep 15
ISSN1538-7445
KeywordsAntigens, CD36, Breast Neoplasms, DNA Damage, Epithelial Cells, Female, Humans, Mammary Glands, Human, Phenotype, Signal Transduction
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.

DOI10.1158/0008-5472.CAN-13-3390
Alternate JournalCancer Res.
PubMed ID25172842
PubMed Central IDPMC4335659
Grant ListNIH/NCI RO1 CA097214 / CA / NCI NIH HHS / United States
P01 CA107584 / CA / NCI NIH HHS / United States
P01 CA107584 / CA / NCI NIH HHS / United States
R01 CA097214 / CA / NCI NIH HHS / United States
U54 CA143803 / CA / NCI NIH HHS / United States
U54 CA143803 / CA / NCI NIH HHS / United States