Simone, B.A., Dan, T., Palagani, A., Jin, L., Han, S.Y., Wright, C., Savage, J.E., Gitman, R., Lim, M.K., Palazzo, J., Mehta, M.P., Simone, N.L. (2016). Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer, Cell Cycle, Volume 15, Issue 17, Pages 2265-2274.

We wanted to determine if using a caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor may impact metastatic disease. An orthotopic mouse model using a highly metastatic, luciferase-tagged triple negative breast cancer (TNBC) model was used. The mice was then treated with CR-only, IR-only and a combination of the two. Molecular analysis was conducted showing that CR decreases proliferation, increases apoptosis, increases survival and globally down regulates the IGF-1R signaling pathway. CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease.

Jin, L., Lim, M., Zhao, S., Sano, Y., Simone, B.A., Savage, J.E., Wickstrom, E., Camphausen, K., Pestell, R.G., Simone, N.L. (2014). The metastatic potential of triple-negative breast cancer is decreased via caloric restriction-mediated reduction of the miR-17~92 cluster. Breast Cancer Research and Treatment, Volume 146, Issue 1, Pages 41-50.

In this study, we found that 3 miRs in the miR-17~92 cluster is down regulated when caloric restriction (CR) is coupled with ionizing radiation (IR) in triple-negative breast cancer (TNBC) models. Four potential targets of the miR cluster related to the extracellular matrix (ECM) were analyzed through cDNA arrays and in silico, which were then confirmed through luciferase assays. Functionally, we demonstrated that CR decreases the metastatic potential of cells signifying the importance of the ECM.

Saleh, A.D., Simone, B.A., Palazzo, J., Savage, J.E., Sano, Y., Dan, T., Jin, L., Champ, C., Zhao, S., Lim, M., Sotgia, F., Camphausen, K., Pestell, R.G., Mitchell, J.B., Lisanti, M.P., Simone, N.L. (2013). Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle, Volume 12, Issue 12, Pages 1955-1963.

Dietary modifications such as caloric restriction (CR) has shown to decrease tumor initiation and progression so we sought to determine if nutrient restriction could be used as a novel therapeutic intervention to improve cytotoxic therapies such as radiation (IR) and affect the molecular profiles of triple-negative breast cancer (TNBC). The most effective diet modification was a 30% reduction of the total daily caloric intake and that tumors treated with both CR and IR showed less proliferation and more apoptosis. We were able to confirm that the IGF-1R pathway (IGF-1R, IRS, PIK3ca and mTOR) became down-regulated.

Ørom, U.A., Lim, M.K., Savage, J.E., Jin, L., Saleh, A.D., Lisanti, M.P., Simone, N.L. (2012). MicroRNA-203 regulates caveolin-1 in breast tissue during caloric restriction. Cell Cycle, Volume 11, Issue 7, Pages 1291-1295.

We characterize the microRNA expression in mouse breast tissue before and after caloric restriction, reporting several changes in the microRNA expression profile. miR-203 is found to be highly induced by caloric restriction, and we demonstrate that caveolin-1 as well as p63 are direct targets of miR-203 in vivo during caloric restriction. In conclusion, we show that the microRNA response induced by caloric restriction can regulate important factors in processes such as longevity and aging and is an integral and important component of the cellular response to caloric restriction.