Background and Aim: The growth and metastatic potential of cancer cells is regulated by the surrounding tumor microenvironment composed of a variety of cells including endothelial cells, fibroblasts, and adipose cells that promote tumor cell growth and invasion. There are two types of adipose tissue within the body. Brown adipocytes (BAT) contains uncoupling protein 1 (UCP1), which burns energy through adaptive thermogenesis. White adipocytes (WAT), which is the most prominent cell type in the breast, stores energy in the form of lipids. White adipocytes have the ability to secrete cytokines, growth factors, and hormones, providing a suitable microenvironment for breast tumor growth and progression. Identifying the mechanism through which adipocytes promote breast tumor progression will allow for the development of novel therapeutic interventions to inhibit adipocyte-breast cancer cell crosstalk during early stages of breast carcinogenesis. Furthermore, development of treatments that target cells within the tumor microenvironment, such as adipose cells, will potentially inhibit primary tumor growth as well as prevent metastatic disease, and could provide a treatment option for breast cancers.
Methods: Functional assays including matrigel invasion, transwell migration and growth assays were conducted. Browning of white adipocyte was achieved by the addition of bioactive compounds such as BITC and Honokiol.
Results: First, we explored the functional impact of WAT on breast cancer cells and observed that co-culture of WAT and breast cancer cells significantly increases the growth, clonogenicity, invasion and migration potential of breast cancer cells. In addition, breast cancer cells with epithelial-like morphology exhibit an acquisition of mesenchymal-like morphology indicating epithelial-to-mesenchymal conversion. To query the existence of a crosstalk between breast cancer cells and WAT, we examined the secretome of WATs and WATs-co-cultured with breast cancer cells (termed CA-WAT). We observed that CA-WAT exhibit increased levels of pro-inflammatory cytokines (IL-6, MCP, and PAI). Furthermore, we examined if WAT can be converted to BAT using bioactive strategies. We found that successful browning of WAT can be achieved with BITC and Honokiol. The addition of bioactive compounds increases the expression of BAT marker genes (UCP1, PRDM16, EVOL3, COX7a, and CIDEA) in WAT. We discovered that browning of WAT not only abrogates the pro-cancer effects of WAT on breast cancer cells but it also successfully alters the secretome profile of WAT.
Conclusion: Our study shows that the conversion of white adipocytes to brown adipocytes with the use of BITC and Honokiol may serve as a novel therapeutic option for altering the breast tumor microenvironment to inhibit the growth and metastatic potential of breast cancer cells.
Citation Format: Nethaji Muniraj, Sumit Siddharth, Sheetal Parida, Marey Shriver, Arumugam Nagalingam, Dipali Sharma. Therapeutic browning of white adipose tissue in the tumor microenvironment to inhibit breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2690.