Breast Cancer-Stromal Interactions: Adipose-derived stromal/stem cell Age and Cancer Subtype Mediated Remodeling.

Adipose tissue is characterized as an endocrine organ that acts as a source of hormones and paracrine factors. In diseases such as cancer, endocrine and paracrine signals from adipose tissue contribute to cancer progression. Young individuals with estrogen receptor-alpha positive (ER-α+) breast cancer have an increased resistance to endocrine therapies, suggesting alternative estrogen signaling is activated within these cells. Despite this, the effects of stromal age on the endocrine response in breast cancer are not well defined. To identify differences between young and aged ER-α+ breast tumors, RNA sequencing data was obtained from The Cancer Genome Atlas (TCGA). Analysis revealed enrichment of matrix and paracrine factors in young (≤40 years old) patients compared to aged (≥65 years old) tumor samples. Adipose-derived stromal/stem cells (ASCs) from non-cancerous lipoaspirate of young and aged donors were evaluated for alterations in matrix production and paracrine secreted factors to determine if the tumor stroma could alter estrogen signaling. Young and aged ASCs demonstrated comparable proliferation, differentiation, and matrix production, but exhibited differences in the expression levels of inflammatory cytokines (IFN-γ, IL-8, IL-10, TNF-α, IL-2, and IL-6). Conditioned media-based experiments showed that young ASC donor age elevated endocrine response in ER-α+ breast cancer cell lines. MCF-7 ER-α+ breast cancer cell line treated with secreted factors from young ASCs had enhanced ER-α regulated genes (PGR and SDF-1) compared to MCF-7 cells treated with aged ASC conditioned media. Western blot analysis demonstrated increased activation levels of p-ER ser-167 in the MCF-7 cell line treated with young ASC secreted factors. To determine if ER-α+ breast cancer cells heightened the cytokine release in ASCs, ASCs were stimulated with MCF-7-derived conditioned media (CM). Results demonstrated no change in growth factors or cytokines when treated with the ER-α+ secretome. In contrast to ER-α+ CM, the ER-α negative MDA-MB-231 derived CM demonstrated increased stimulation of pro-inflammatory cytokines in ASCs.

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