Erika Clark

Introduction Breast cancer is the second leading cause of death for women in the United States and is the most diagnosed cancer in women¹. Postmenopausal breast cancer has increasingly been associated with obesity, which is an accumulation of adipose tissue leading to negative consequences related to wellbeing^2-4. Additionally, it has been shown that estrogen receptor positive (ER+) status is the closest link between postmenopausal breast cancer and obesity⁵. Studies have found that adipose tissues are home to many adipose-derived stem cells (ASCs), which release a number of pro-inflammatory and pro-carcinogenic factors^{1-4, 6}. Other studies have found that luminal progenitor cell activity is increased in breast tissue of obese individuals⁷. These findings suggest that prevention of obesity may reduce the incidence of breast cancer. Methods For the ASC hypothesis, ER+ breast cancer cells of the MCF7 (ER+/PR+) line were co-cultured with ASCs of abdominal or non-abdominal origin derived from lean and obese individuals^1-2. For the luminal progenitor cell hypothesis, a high-fat diet (HFD) mouse model was utilized. Basal/myoepithelial cells, luminal cells, and ERα expression were quantified via immunohistochemistry⁷. Results Breast cancer cells were co-cultured with obese patient-derived ASCs and showed an increase in MCF7 cells₁. When MCF7 were cultured with ASCs and estrogen, the number of breast cancer cells increased, specifically in the obese-derived subtypes¹. Using leptin-neutralizing antibodies with estrogen showed a decrease in proliferation of ASCs without the presence of leptin; it has been found that women with ER+/PR+ cancers had poorer prognoses if they had higher levels of leptin expression¹. MCF7 induces SERPINE1 and MMP-2 expression, which are pro-carcinogenic genes, in the tumors when co-injected with ASCs derived from obese individuals². When leptin was silenced in this model, expression of the two genes decreased². Using an HFD mouse model, obese mice were found to have a significant increase in proportion of luminal cell to basal/myoepithelial cell population as BMI increased⁷. There was a greater expression of ERα expression in HFD mouse mammary cells than controls as well as a greater expression of proliferative markers⁷. Conclusions. Studies have found that adipose tissue is host to adipose-derived stem cells that positively react to estrogen and appear to increase leptin expression, which is a known factor in poor breast cancer prognosis. Additionally, luminal progenitor cells appear to play a role in ER+ breast cancer proliferation.

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2. Strong AL, Ohlstein JF, Biagas BA, et al. Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers. Breast Cancer Research. 2015;17(1). doi:10.1186/s13058-015-0622-z.
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6. Eterno V, Zambelli A, Pavesi L, et al. Adipose-derived mesenchymal stem cells (ASCs) may favour breast cancer recurrence via HGF/c-Met signaling. Oncotarget. 2013;5(3). doi:10.18632/oncotarget.1359.
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