Mitochondrial DNA variant interactions modify breast cancer risk

Covarrubias, Daniel; Bai, Renkui; Wong, Lee‐Jun C.; Leal, Suzanne M.

doi:10.1007/s10038-008-0331-x

Cited by 50 publications

(65 citation statements)

References 19 publications

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“…This is in agreement with a more recent study indicating a wide range of heteroplasmy in breast cancer (46). Our data is also in line with the observation that mtDNA polymorphisms affect the risk of breast cancer (47, 48). …”

Section: Discussionsupporting

confidence: 92%

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 92%

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

et al. 2017

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“…Canter demonstrated that the 10398 polymorphism influences breast cancer susceptibility in African American women (17). Other reports link A10398G to breast cancer risk in Caucasians (18–19). Czarnecka demonstrated A10398G as an inherited predisposition factor for breast cancer in Polish women (18).…”

Section: 0 Discussionmentioning

confidence: 98%

“…Czarnecka demonstrated A10398G as an inherited predisposition factor for breast cancer in Polish women (18). A study of European Americans observed an increased risk for A10398G and reported an interaction between the variants A12308G and A10398G affecting women’s risk of breast cancer (19). Finally, an association between the 10398 SNP and African American men’s prostate cancer risk was reported in a letter in Cancer Research (20).…”

Section: 0 Discussionmentioning

confidence: 99%

Bone metastasis in prostate cancer: Recurring mitochondrial DNA mutation reveals selective pressure exerted by the bone microenvironment

Arnold¹,

Fedewa²,

Goodman³

et al. 2015

Bone

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Background Cancer progression and metastasis occurs such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell’s description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis. Methods We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation. Results Somatic mutations were significantly more numerous in bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (np) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in bone. Other notable somatic mutations that occurred in more than one patient include a tRNA Arg mutation at np 10436 and a tRNA Thr mutation at np 15928. The tRNA Arg mutation was restricted to bone metastases and occurred in three of 10 patients (30%). Somatic mutation at 15928 was not restricted to bone and also occurred in three patients. Conclusions Mitochondrial genomic variation was greater in metastatic sites than the primary tumor and bone metastases had statistically significantly greater numbers of somatic mutations than either the primary or the soft tissue metastases. The genome was not mutated randomly. At least one mutational “hot-spot” was identified at the individual base level (nucleotide position 10398 in bone metastases) indicating a pervasive selective pressure for bone metastatic cells that had acquired the 10398 mtDNA mutation. Two additional recurrent mutations (tRNA Arg and tRNA Thr) support the concept of bone site-specific “survival of the fittest” as revealed by variation in the mitochondrial genome and selective pressure exerted by the metastatic site.

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“…In European-American, Polish, Malay, North Indian and AA populations, the G10398A substitution in the N haplogroup affecting the ND3 locus is linked to a higher susceptibility to breast cancer [12, 50, 79, 80, 83, 191, 361]. For AA women, there is a cumulative increase in risk when the T4216C substitution in the ND1 locus is present along with G10398A.…”

Section: Disparities At the Mitochondrial Genome Level And Their Rmentioning

confidence: 99%

Mitochondrial determinants of cancer health disparities

Choudhury

Singh

2017

Seminars in Cancer Biology

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Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. The goal of this review is to provide an understanding and a framework of mitochondrial determinants that may contribute to cancer disparities in racially different populations. Mitochondria, which are multi-functional, have been implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Due to ethnic-based diversity, the mitochondrial genome (mtDNA) could be a basis for inherited racial disparities and for acquired somatic mutations during tumorigenesis. In African Americans, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, which in turn can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African Americans and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.

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Mitochondrial DNA variant interactions modify breast cancer risk

Cited by 50 publications

References 19 publications

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

Bone metastasis in prostate cancer: Recurring mitochondrial DNA mutation reveals selective pressure exerted by the bone microenvironment

Mitochondrial determinants of cancer health disparities

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