Abstract 4641: Metabolic reprogramming of the breast contributes to a cancer promoting milieu

Abstract

Abstract In addition to the accumulation of pro-oncogenic mutations in the epithelial cells, the tumorigenic process involves the dysregulation of the interactions between the epithelial cells and their microenvironment, as well as alterations within the microenvironment itself. The latter is composed of endothelial cells, immune cells, fibroblasts, unaffected epithelium, and adipocytes. Increasing evidences support that cell transformation progresses in a potentially cancer-promoting microenvironment context, also known as field cancerization model. Therefore, it is critical to investigate changes occurring in both the epithelial compartment and the surrounding microenvironment to understand how breast cancer initiates. In our preliminary study, we analyzed the transcriptome profile of microdissected breast tissue compartments (epithelium, stroma and adipose tissue) from tissue biopsies obtained from women who donated their histologically normal tissue two-to-five years before breast cancer diagnosis (here labeled pre-cancer), and matched healthy control donors. In the pre-cancer breast epithelium we detected a significant increase in lipid metabolism-related genes including lipases (HSL, LPL) and perilipins (PLIN1, PLIN4), which mediate the release of fatty acids from triacylglycerol storage, and ELOVL5 and ELOVL7, which generate oleic acid. Moreover, Acyl-CoA Synthetase Medium Chain Family Member 1, ACSM1, involved in the activation of lipoic acid, an essential cofactor for mitochondrial metabolism, is also upregulated in pre-cancer breast tissue. Upregulation of genes involved in metabolic activation is observed also in the stroma and adipose tissue compartments. Interestingly, the transcriptome profiling of the pre-cancer breast stroma shows the downregulation of genes coding for several immune cell markers as compared with the healthy controls. Immunohistochemical staining of CD45 confirms a significant reduction in immune cells in the pre-cancer versus matched healthy control breasts. This finding suggests the prevalence of an immune-suppressive environment in the breast long before the clinical diagnosis of breast cancer. Understanding the changes occurring in the cancerized field is critical for elucidating 1) the involvement of microenvironment in cancer initiation 2) the role of histologically normal yet genetically altered surgical margins in risk of disease recurrence upon lumpectomy for early breast cancer diagnosis, and 3) the mechanisms of field cancerization in the contralateral breast. Citation Format: Natascia Marino, Rana German, Xi Rao, George Sandusky, Max Jacobsen, Sha Cao, Anna Maria Storniolo. Metabolic reprogramming of the breast contributes to a cancer promoting milieu [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4641.