Auranofin Improves the Therapeutic Ratio of Abdominal Irradiation

Abstract

low-grade inflammation of adipose tissue which alters the biology of resident ASCs. ASCs from obese individuals (obASCs) have been shown to promote proliferation and metastasis of breast cancer in comparison to lean ASCs (lnASCS) in vitro and in vivo. The pro-survival secretome secreted by ASCs led us to investigate the role of lnASCs and obASCs in breast cancer radioresistance. Materials/Methods: 5.0 x 10 4 estrogen receptor positive (ER+) breast cancer cell line MCF7 were cocultured for 96 hours in a transwell system(0.4 mm pore size, Costar) with 5.0 x 10 4 three pooled donors of lnASCs or obASCs, or were cultured without ASCs. Using doses of a 35 kV x-ray machine (Faxitron MX-20) Culture systems were irradiated at doses of 0, 2, 5, 10 Gy and further incubated 24 hours. Cell survival after irradiation was determined by colony forming unit assay. Total cellular RNA was extracted from MCF7 cells after coculture with a pool of ASCs (nZ3 per group) using RNeasy Mini Kit (Qiagen, Valencia, CA, USA) and treated with DNase I digestion (Qiagen) according to manufacturer's instructions. One mg of RNA was converted to cDNA with SuperScript VILO cDNA synthesis kit (Invitrogen). Quantitative real-time PCR was performed using EXPRESS SYBR GreenER qPCR SuperMix Kit (Invitrogen) according to manufacturer's instructions. Results: ER+ breast cancer cell line, MCF7, has an increased survival fraction and are better protected from therapeutic doses of ionizing radiation when cocultured with obASCs. IL-6 has been reported to play a protective role in resistance to radiation and thus was a prime candidate for the mediator for the radioresistance conferred by obASCs. We saw a significant increase in IL-6 expression in ER+ breast cancer co-cultured with ASCs. Conclusion: Obesity is an important risk factor for breast cancer. Obesity not only increases the incidence of breast cancer, but also the mortality rate. Obesity has been shown to promote metastasis and drug resistance of breast cancer. Here we demonstrate obASCs enhancing survival of ER+ breast cancer after exposure to radiation. This study sheds new light on ASCs promotion of breast cancer, which has important clinical implications on the increased mortality rates of obese women with breast cancer.