Abstract 2024: Obesity induces breast cancer cell invasion through stromal secretion of IGF-1

Abstract

Abstract Obese women diagnosed with breast cancer have an increased risk for metastasis, and the underlying mechanisms are not well established. Within the mammary gland, adipose stromal cells (ASCs) are a group of heterogeneous cells with the capacity to differentiate along multiple mesenchymal lineages. ASCs are recruited and activated within tumors, but it is unknown how obesity may influence ASCs in both normal and cancerous tissue. To study the effects of obesity on ASCs, we isolated the stromal vascular fraction from the mammary glands of mice fed either a control diet (CD) or high fat diet (HFD) to induce obesity and plated the cells to select for adherent growth. We observed that obesity increased ASCs proliferation, decreased differentiation potential, and upregulated expression of α-smooth muscle actin, a marker of activated fibroblasts, compared to ASCs from lean mice. To determine how ASCs from obese mice impacted tumor growth, we mixed ASCs isolated from CD- or HFD-fed mice with mammary tumor cells, Met-1 cells, and transplanted them into the mammary glands of lean FVB female mice. Tumors cells mixed with ASCs from obese mice grew significantly larger tumors and had increased invasion into surrounding adipose tissue than tumor cells mixed with control ASCs. To study the effects of factors secreted by ASCs on tumor cell behavior, we collected conditioned media (CM) from lean and obese ASCs and treated Met-1 cells. Compared with lean ASCs, obese ASCs expressed higher levels of insulin-like growth factor-1 (IGF-1), which has been implicated in tumor cell invasion. Met-1 cells treated with recombinant IGF-1 were more invasive than vehicle-treated cells. In addition, Met-1 cells treated with obese ASCs CM supplemented with an IGF-1 neutralizing antibody had significantly reduced invasion, compared to controls. Weight loss induced in obese mice significantly decreased expression of IGF-1 from ASCs and reduced the ability of the ASCs to induce an invasive phenotype. Together, these results suggest that obesity enhances local invasion of breast cancer cells through increased expression of IGF-1 by mammary ASCs, and weight loss may reverse this tumor-promoting phenotype. Citation Format: Lauren Hillers, Joseph D'Amato, Tamara Chamberlin, Gretchen Paderta, Lisa Arendt. Obesity induces breast cancer cell invasion through stromal secretion of IGF-1 [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 2024.