By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPR mt ). The UPR mt promotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPR mt , we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPR mt is a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.

Highlights d Evidence of endogenous mitohormesis in breast cancer cell lines and primary tumors d Mitohormetic priming of tumor cells leads to increased basal activation of the UPR mt d Mitohormesis and UPR mt activation makes cancer cells more invasive and metastatic d UPR mt enriched breast cancer patients have worse clinical outcomes

No abstract

We previously reported that the dismutase SOD1 is overexpressed in breast cancer. However, whether SOD1 plays an active role in tumor formation in vivo has never been demonstrated. Further, as luminal cells of normal breast epithelial cells are enriched in SOD1, whether SOD1 is essential for normal mammary gland development has never been determined. We initiated this study to investigate the role of SOD1 in mammary gland tumorigenesis as well as in normal mammary gland development. We crossed the inducible erbB2 (MMTV-iErbB2) and Wnt (MMTV-Wnt) transgenic mice to the SOD1 heterozygote or knockout mice. Our results show that SOD1 is essential for oncogene-driven proliferation, but not normal proliferation of the mammary gland associated with pregnancy or other normal proliferative tissues such as skin and intestines. We show that activation of the oncogene ErbB2 is associated with increased ROS and that high ROS sub-population of ErbB2 cancer cells show elevated SOD1. In the same cells, decrease in SOD1 is associated with an elevation in both apoptosis as well as oncogene-induced senescence. Based on these results, we suggest that SOD1 carries a housekeeping function that maintains ROS levels below a threshold that supports oncogene-dependent proliferation, while allowing escape from oncogene-induced senescence, independently of the oncogene driving tumor formation. These results identify SOD1 as an ideal target for cancer therapy as SOD1 inhibitors hold the potential to prevent the growth of cancers cells of diverse genotypes, activate multiple modes of cell death therefore making acquired resistance more difficult, while sparing normal tissues.

Defects in the proteasome can result in pathological proteinopathies. However, the pathogenic role of sex‐ and tissue‐specific sensitivity to proteotoxic stress remains elusive. Here, we map the proteasome activity across nine tissues, in male and female mice, and demonstrate strong sexual dimorphism in proteasome activity, where females have significantly higher activity in several tissues. Further, we report drastic differences in proteasome activity among tissues, independently of proteasome concentration, which are exacerbated under stress conditions. Sexual dimorphism in proteasome activity is confirmed in a SOD1 ALS mouse model, in which the spinal cord, a tissue with comparatively low proteasome activity, is severely affected. Our results offer mechanistic insight into tissue‐specific sensitivities to proteostasis stress and into sex differences in the progression of neurodegenerative proteinopathies.