The role of the mitochondrial unfolded protein response (UPRmt) in the etiology of breast cancer in young versus elderly women.

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Aging and obesity are two major risk factors of developing breast cancer. Further, the vast majority of breast cancers in post-menopausal women are estrogen receptor positive alpha (ERα The reason why aging favors the development of ERα breast cancer is not known. The overall hypothesis of this application is that mitochondrial biology plays a fundamental role in these observations. Our group focuses on the mitochondrial unfolded protein response (UPRmt). We have identified two parallel axes of mitochondria to nucleus communication in breast cancer. One axis is regulated by the mitochondrial sirtuin SIRT3, a gene tightly linked to aging. The other is regulated by the ERα. Our overall understanding of the UPRmt is that it acts as a housekeeping function to ensure mitochondrial repair and fitness in face of elevated ROS found in cancer cells, allowing the mitochondria to maintain its integrity and generate the metabolites necessary for amino acids, lipids and nucleotides synthesis; the building blocks of increased cellular mass, characteristic of tumor growth. We have characterized the UPRmt in breast cancer cells lines and in the inducible ErbB2 mouse model of breast cancer in vivo. More recently, we took advantage of this mouse model to induce the ErbB2 oncogene in young and old mice. We found that despite sharing the same oncogene, tumors are significantly larger in old mice. Further, we perform RNAseq analysis and found genetic signatures that distinguish both groups. Notably, tumors derived from old mice show decrease in SIRT3 but up-regulation of ER and AKT. Based on these findings, we hypothesize that as SIRT3 is reduced in older women, upon oncogene activation and ROS production, ERα cells activate the ERα axis of the UPRmt to survive oxidative stress, therefore providing a selective advantage for the proliferation of ERα cells. As calorie restriction (CR) is known to increase the expression for SIRT3, CR is predicted to affect the UPRmt. To further explore these hypotheses, we propose: Specific aim 1: Characterize what distinguish the genomic profiles of mammary tumors derived from young versus old females. Specific aims 2: Test whether calorie restriction affects the genomic profiles of mammary tumors from young to old and vice versa.