Effect of Density and Altered Structure of Adipose Stromal Cells on Breast Cancer Initiation.

Abstract

Abstract Increased adiposity is strongly associated with higher risk of estrogen-receptor positive postmenopausal breast cancer and increased mortality of breast cancer. Adipose stromal cells (ASC) play critical role in both development and metastasis of cancer as well as initiation of the disease. Within tumor microenvironment role of ASC is well studied, however, its role in initiation of the disease is less understood. In this study we uncovered novel function of ASC in both estrogen-dependent and independent cancer development. We showed that ASC induces aromatase, a key enzyme in estrogen biosynthesis, under the influence of cell density-stimulated shape change mechanism in cancer-free individuals. The activation of aromatase transcription is mediated by IkB kinase b (IKKb), a kinase previously known for its cancer-promoting activity in tumor cells. Activation of IKKb leads to elevated expression of transcription factor C/EBPb, which binds to and stimulates two breast cancer-associated promoters of the aromatase gene. We also show that shape-induced estrogen production in ASCs can stimulate estrogen-dependent transcription in ER-positive breast tumor cells. We developed a xenograft model that supported our in vitro observation.Here we further showed that density-driven ASCs significantly stimulated migration and invasion of ER-negative breast cancer cells in vitro and tumor invasion in a co-transplant xenograft mouse model. Our study also identified cofilin-1, a known regulator of actin dynamics, as an important determinant for the stimulatory activity of ASCs. The cofilin-dependent pathway controled the production of interleukin 6 (IL-6) in ASCs. Depletion of IL-6 from ASC-conditioned medium abrogated the stimulatory effect of ASCs on the migration and invasion of breast tumor cells. Thus, our study revealed how ASC, under an altered cellular architecture, may contribute to the breast cancer risk in obesity and high breast density. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 505.