CANCER

Obesity is a major modifiable risk factor for breast cancer and is responsible for approximately 20% of cancer deaths. However, mechanisms by which obesity promotes breast cancer tumorigenesis are incompletely understood. Studies from our group showed that obesity produces a pro-inflammatory ‘metabolically activated’ (MMe) ATM phenotype that is both mechanistically and functionally distinct from the M1 phenotype. Although we showed that MMe macrophages accumulate in visceral and subcutaneous adipose tissue of obese humans and mice, their presence in mammary fat, and their role in TNBC tumorigenesis have not been explored. Here, we show that MMe macrophages accumulate in mammary fat of obese mice and humans. We demonstrate that MMe macrophages secrete IL6 in an NADPH oxidase 2-dependent manner that signals through glycoprotein 130 (GP130) on murine and human TNBC cells to promote stem-like properties and tumor formation during obesity. These findings reveal an important mechanism by which obesity enhances TNBC tumorigenesis. (Tiwari et al., 2019)

Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment, and the importance of such regulation to metastasis suppression is incompletely understood. We showed that Raf Kinase Inhibitory Protein (RKIP), a metastasis suppressor that is inactivated in triple negative breast cancer, inhibits the recruitment of a specific population of tumor-associated macrophages with pro-metastatic properties. We established that RKIP inhibits TAM recruitment by reducing CCL5 expression, and further demonstrated that CCL5 overexpression was sufficient to rescue recruitment of pro-metastatic TAMs and tumor cell intravasation on a non-metastatic RKIP+ background. These findings highlight the interaction between tumor cell genetics and the tumor microenvironment and identify possible therapeutic targets for the treatment of patients with triple negative breast cancer. (Frankenburger et al., 2015)

Selected Publications

Tiwari, P., Blank, A., Cui, C., Schoenfelt, K.Q., Zhou, G., Xu, Y., Khramstova, G., Olopade, F., Shah, A.M., Kahn, S.A., Rosner, M.R., & Becker, L. Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer. In Press, J. Exp. Med. [Pre-Print]

Frankenburger, C., Rabe, D., Bainer, R., Sankarasharma, D., Chada, K., Krausz, T., Gilad, Y., Becker, L., & Rosner M.R. (2015) Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of pro-metastatic tumor-associated macrophages. Cancer Res. 75, 4063-4073.