DNA Damage Drives an Activin A–Dependent Induction of Cyclooxygenase-2 in Premalignant Cells and Lesions

Abstract

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the synthesis of prostaglandins. Its overexpression induces numerous tumor-promoting phenotypes and is associated with cancer metastasis and poor clinical outcome. Although COX-2 inhibitors are promising chemotherapeutic and chemopreventative agents for cancer, the risk of significant cardiovascular and gastrointestinal complications currently outweighs their potential benefits. Systemic complications of COX-2 inhibition could be avoided by specifically decreasing COX-2 expression in epithelial cells. To that end, we have investigated the signal transduction pathway regulating the COX-2 expression in response to DNA damage in breast epithelial cells. In variant human mammary epithelial cells that have silenced p16 (vHMEC), double-strand DNA damage or telomere malfunction results in a p53-and activin A-dependent induction of COX-2 and continued proliferation. In contrast, telomere malfunction in HMEC with an intact p16/Rb pathway induces cell cycle arrest. Importantly, in ductal carcinoma in situ lesions, high COX-2 expression is associated with high γH2AX, TRF2, activin A, and telomere malfunction. These data show that DNA damage and telomere malfunction can have both cell-autonomous and cell-nonautonomous consequences and can provide a novel mechanism for the propagation of tumorigenesis. Cancer Prev Res; 3(2); 190-201. ©2010 AACR.

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…Notably, selective knockdown of IL-6 in CAFs, but not in DCIS cells, abrogates these phenotypes. This report brings further mechanistic insights to a prior study reporting that DCIS lesions with a heightened DNA damage/activin A/ cyclooxygenase-2 (COX-2) signature were associated with a more reactive stroma (Fordyce et al 2010(Fordyce et al , 2012 and more frequent progression to invasive cancer (Kerlikowske et al 2010).…”

“…Accompanying CD36 repression is the secretion of soluble factors, such as activin A, which has been implicated as a key effector in a DNA damage-inducible secretory program that acts in a cell-extrinsic fashion to generate many of the above phenotypes ( Fig. 2; Fordyce et al 2010Fordyce et al , 2012. Extending these findings, recent evidence has been provided for CD36 repression as part of a dramatic switch in fibroblast identity.…”

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

“…In addition, p16 Ink4a overexpression has been reported in senescent fibroblasts , in response to oxidative stress (Ksiazek et al, 2006;Quereda et al, 2007), DNA damage and changes in chromatin structure (Canepa et al, 2007;Fordyce et al, 2010). Nonetheless, a complete understanding of the signals that trigger senescence is currently lacking, and although p16 Ink4a appears to be one of the principal factors in senescence, more information is needed to ascertain the exact role of each factor in this process.…”

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

“…Previously, we demonstrated that DNA damaging agents and/or telomere malfunction in mortal, non-tumorigenic variant human mammary epithelial cells (vHMEC) induce a DDR and activin A-dependent COX-2 expression (19). Fibroblasts from reduction mammoplasties (RMF) co-cultured with DNA-damaged vHMEC induce many genes consistent with a desmoplastic phenotype (e.g.…”