Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling.

Abstract

Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this study, the effects of obesity-altered ASCs (obASCs) on estrogen receptor positive breast cancer cell's (ER+BCCs) response to radiotherapy (RT) were evaluated. We determined that BCCs had a decreased apoptotic index and increased surviving fraction following RT when co-cultured with obASCs compared to lnASCs or non-co-cultured cells. Further, obASCs reduced oxidative stress and induced IL-6 expression in co-cultured BCCs after radiation. obASCs produce increased levels of leptin relative to ASCs from normal-weight individuals (lnASCs). obASCs upregulate the expression of IL-6 compared to non-co-cultured BCCs, but BCCs co-cultured with leptin knockdown obASCs did not upregulate IL-6. The impact of shLeptin obASCs on radiation resistance of ER+BCCs demonstrate a decreased radioprotective ability compared to shControl obASCs. Key NOTCH signaling players were enhanced in ER+BBCs following co-culture with shCtrl obASCs but not shLep obASCs. This work demonstrates that obesity-altered ASCs, via enhanced secretion of leptin, promote IL-6 and NOTCH signaling pathways in ER+BCCs leading to radiation resistance.

• Authors: Rachel A Sabol, Vidal A Villela, Alexandra Denys, Benjamin T Freeman, Alifiani B Hartono, Rachel M Wise, Mark A A Harrison, Maxwell B Sandler, Fokhrul Hossain, Lucio Miele, Bruce A Bunnell
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 8 (Apr 15 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32326381 (Publication Type: Journal Article)

Chemical References

• IL6 protein, human
• Interleukin-6
• Leptin
• RNA, Small Interfering
• Receptors, Estrogen
• Receptors, Notch

Topics

• Adipose Tissue (cytology, metabolism)
• Animals
• Apoptosis (radiation effects)
• Breast Neoplasms (metabolism, pathology, radiotherapy)
• Cell Proliferation (radiation effects)
• Cell Survival (radiation effects)
• Coculture Techniques
• DNA Damage (radiation effects)
• Female
• Gene Knockdown Techniques
• Humans
• Interleukin-6 (metabolism)
• Leptin (genetics, metabolism)
• MCF-7 Cells
• Mesenchymal Stem Cells (metabolism)
• Mice
• Obesity (metabolism)
• Oxidative Stress (radiation effects)
• Paracrine Communication (radiation effects)
• RNA, Small Interfering
• Radiation
• Receptors, Estrogen (metabolism)
• Receptors, Notch (metabolism)
• S Phase Cell Cycle Checkpoints (radiation effects)
• Signal Transduction (radiation effects)
• Tumor Microenvironment
• Xenograft Model Antitumor Assays