Stress Signaling from Human Mammary Epithelial Cells Contributes to Phenotypes of Mammographic Density

Abstract

Telomere malfunction and other types of DNA damage induce an activin A-dependent stress response in mortal non-tumorigenic 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 to 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, CD36) to prevent breast cancer.

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…When fibroblasts from disease-free women of high and low mammographic density were compared, gene expression profiling identified CD36 as the gene most differentially expressed. Similar to the observations described above for the stromal components that repress CD36 and display multiple, coordinated, protumorigenic phenotypes, alterations in the expression of this master regulator, CD36, in the stromal components of healthy breast tissue prior to tumor formation are associated with increased risk for future tumor incidence and progression (DeFilippis et al 2014).…”

“…Likewise, endothelial cells with low CD36 exhibit increased angiogenesis, preadipocytes with low CD36 fail to differentiate into adipocytes, and, finally, immune cells with low CD36 are in a M2 (protumorigenic) state rather than a M1 (anti-tumorigenic) state. This study also documents that CD36 controls a coordinated, multicellular program and that CD36 is necessary and sufficient to control a wide range of protumorigenic phenotypes (DeFilippis et al , 2014. These phenotypes, often observed in desmoplasia, include low adipocyte content, increased ECM proteins (collagen and fibronectin), an increased number of fibroblasts and vascular cells , and potentially immune cells.…”

“…Several studies have shed light on these questions and contributed to a stunning realization that stromal changes and the existence of CAFlike cells can precede the formation of malignant epithelial cells. While it is clear that coculturing fibroblasts and malignant epithelial cell lines can result in reciprocal gene expression changes (Rozenchan et al 2009), characterization of tissues at high risk for carcinoma formation demonstrate that stromal changes associated with the CAF phenotype already exist and are therefore not dependent on signals from a carcinoma for their generation (Saadi et al 2010;DeFilippis et al 2014).…”

“…Evidence for the acquisition of a CAF phenotype prior to malignancy has been underscored by a recent study showing that fibroblasts derived from breast tissues obtained from healthy women with high mammographic density (and no breast cancer) exhibit desmoplastic/protumorigenic phenotypes compared with fibroblasts derived from breast tissues obtained from women with low mammographic density (DeFilippis et al , 2014. When fibroblasts from disease-free women of high and low mammographic density were compared, gene expression profiling identified CD36 as the gene most differentially expressed.…”

“…Recent provocative reports have further extended this novel concept by unequivocally demonstrating that, in some cancers, the stroma goes beyond playing the role of a facilitator of the tumorigenic process. Alterations in stromal cell signaling and transcriptional program can precede (or act independently of) epithelial cell alterations and actually act as a driver of the tumorigenic process (DeFilippis et al 2014;Scherz-Shouval et al 2014;Hu et al 2015;Procopio et al 2015). As a result of this conceptual shift, we have witnessed a recent surge in therapeutic strategies aimed at reverting alterations associated with a protumorigenic stroma, in particular the activity of anti-and protumorigenic immune cells whose balance determines, to a large extent, disease outcome (Callahan and Wolchok 2015).…”