Understanding the influence of Mitochondrial DNA haplotypes on breast aging and cancer

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The rate of aging of the breast differs between women. Further, older women tend to develop estrogen receptor alpha (ERα) positive breast cancer sub-type, despite lower hormonal levels. Our preliminary data compel us to hypothesize that mitochondrial genetics alters the rate of aging of the breast and impacts the sub- type of breast cancer. The mammary ductal tree is composed of luminal hormone sensitive (HS), ERα positive cells as well as luminal alveolar (AV) and basal cells that are both ERα negative. A recent scRNAseq analysis revealed that in both the basal and luminal AV cells, mitochondrial function declines with age but this decline was not observed in luminal HS cells. Rather, the luminal HS cells seem to up-regulate of the unfolded protein response of the endoplasmic reticulum (UPRER). The UPRER is closely interconnected with the mitochondrial UPR (UPRmt). Our group has identified the ERα and the mitochondrial sirtuin-3 (SIRT3) as key players of the UPRmt. While the level of the ERα does not fluctuate with age, in most individuals, SIRT3 levels decrease with age. Therefore, our central hypothesis is that the decline in mitochondrial function observed in the basal and luminal AV cells over aging may be due to the decline in the SIRT3 axis of the UPRmt. However, in the luminal HS cells this decline is not observed as they maintain mitochondrial function through the ERα axis of the UPRmt. We hypothesize that the ability of luminal HS cells to maintain mitochondrial function through aging, allow them to survive transformation and explains the selective bias toward ERα positive breast cancer in older women. Further, we performed RNAseq on the young and old-females derived mammary tumors and established luminal HS cells derived from both young and aged females. We found that markers of the ER? axis of the UPRmt and UPRER are up-regulated specifically in the aged luminal HS cells. This observation suggests that the transcriptional program of the ER? may be altered by aging. We hypothesize that the increase in ROS and the decline in hormones during aging alter the transcriptional program of the ERα. Further, the rate of decline in SIRT3 with age varies between individuals. Likewise, we found that the levels of SIRT3 differ between the BL/6NZB and BL/6C57 mice which have the same nuclear genome (BL/6), but different mtDNA; (C57 or NZB). Therefore, the implication is that the rate of decline of the SIRT3 axis of the UPRmt with age differs based on mtDNA haplotypes. Lastly, we hypothesize that while BL/6C57 mice (low SIRT3) will develop exclusively ERα positive mammary tumor over aging, in BL/6NZB females (high SIRT3) both basal and ER? positive mammary tumors will be observed. To test these hypotheses, we propose the following aims: Specific aim 1: Analyze of the UPRmt and UPRER and the ERα transcriptome in ERα positive luminal mammary cells over aging. Specific aim 2: Perform scRNAseq analysis of the mammary gland over aging in BL/6C57 and BL/6NZB mice. Specific aim 3: Compare the sub-types of mammary tumors between BL/6C57 and BL/6NZB mice over aging. We propose to do these analyses in pre-, peri- and post-menopausal as well as elderly mice.