Degree

Doctor of Philosophy (PhD)

Department

Biological and Agricultural Engineering

Document Type

Dissertation

Abstract

In disease states such as cancer, endocrine and paracrine signals from adipose tissue contribute to cancer progression and drug resistance. Young individuals diagnosed with estrogen receptor-alpha positive (ER-a+) breast cancer have an observed increase in resistance to endocrine therapies. This suggests that an alternative estrogen signaling pathway is active within these tumors. Despite this, the effects of stromal age on the endocrine response in breast cancer is not well known. Here, we review and highlight the involvement of the stromal age in both tumorigenesis and physiological wound healing. To identify specific differences between young and aged ER-a+ breast tumors, RNA sequencing data was obtained from The Cancer Genome Atlas (TCGA). Analysis revealed enrichment of matrix and paracrine factors in young (old) patients compared to aged (>65 years old) tumor samples. Analyzing cell infiltrate of young and aged ER-a+ breast tumors revealed significant differences in several immune cell populations, however, there were no differences in MSC and adipocyte infiltrate between young and aged tumors. Based on these results, we next sought to determine if stromal cells exhibited age-dependent differences. To determine if the age of tumor stroma differentially regulated the ER-a+ tumor microenvironment (TME), adipose-derived stem/stromal cells (ASCs) from healthy young and aged donors were evaluated for alterations in matrix production and paracrine factors. Results demonstrated that young and aged ASCs were neither phenotypically different, nor did they demonstrate alterations in matrix production. Analysis of paracrine factors demonstrated that young and aged ASCs had differences in pro-inflammatory cytokines. Paracrine factors from young ASCs enhanced the ER-a regulated genes progesterone receptor (PR) and stromal-derived factor 1 (SDF-1) in the MCF-7 ER-a+ breast cancer cell line. Additionally, western blot analysis demonstrated increased activation of p-ER ser167 in the MCF-7 cell line treated with young ASC paracrine factors. These results are important in understanding the mechanisms of estrogen receptor signaling in young breast cancer patients, as well as unveiling underlying factors that contribute to the unique TME in young breast cancer patients.

Date

3-11-2021

Committee Chair

Martin, Elizabeth C.

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