Abstract P6-02-08: Molecular drivers of adipogenotoxicosis in breast tumor-associated adipose

Abstract

Abstract Background: Having long been thought to function only as an inert energy storage depot, the role of adipose tissue in tumorigenesis has been largely ignored; however, adipose is an active endocrine organ that can directly influence tumor growth. Improved understanding of the role of adipose in tumorigenesis is crucial given the association between obesity and breast cancer risk in post-menopausal women, increasing rates of obesity and use of autologous fat transfer in breast reconstruction. Methods: Adipose, adjacent to and distant from (>3 cm from the closest tumor margin) invasive breast tumors, was laser microdissected from 20 post-menopausal women, and from 22 post-menopausal women with non-malignant breast disease. Gene expression data were generated using U133A 2.0 microarrays. Data were analyzed to identify significant patterns of differential expression between adipose classes at the individual gene and molecular pathway level. Gene expression differences were validated using qRT-PCR in an additional set of 29 specimens. Results: SPP1, RRM2, MMP9 and PLA2G7 were expressed at >3-fold (P < 0.01) higher levels in adjacent adipose compared to distant adipose from the same breast. A number of immune response genes including MARCO, FABP7, ELF5, MYBPC1, MMP7, CLDN8, HLA-DQB1 and HLA-DQA1 were differentially expressed in distant adipose compared to adipose from non-malignant breasts. The most significant gene expression differences were detected between tumor-adjacent and non-malignant adipose with >3-fold higher expression of EGFL6 and ITGB2 and >3-fold lower levels of PIP, which are involved in growth, proliferation, and cellular adhesion in adjacent compared to non-malignant adipose. Pathway analysis revealed that immune response differs between non-malignant, distant and tumor-adjacent adipose with an enhanced B- and T-cell response detected in adjacent compared to distant or non-malignant adipose. Inflammatory response as well as DNA transcription and replication pathways were differentially expressed in distant compared to non-malignant adipose. Conclusions: Gene expression levels differ in breast adipose depending on presence of and proximity to tumor cells. Adipose adjacent to the tumor demonstrated the largest immune response, supporting the idea of adipogenotoxicosis, which through pro-inflammatory and genotoxic responses, promotes tumor development. In addition, genes involved in cellular proliferation, degradation of the extracellular matrix and angiogenesis are differentially expressed in adjacent compared to distant or non-malignant adipose, thus tumor-adjacent adipose may be contributing to the growth and invasion of the primary tumor. These data thus suggest that adipose is not an inert component of the breast microenvironment but plays an active role in tumorigenesis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-02-08.