Since a significant number of women serve in the military an increasing number of female veterans are impacted by breast cancer. The long-term goal of this research is to develop chemo-preventive and therapeutic agents against breast cancer to reduce the health burden in female military personnel. The current goal of this research is to identify mechanisms involved in the development of arsenic-induced breast cancer. To replicate normal field exposure conditions, we exposed breast epithelial cells to low dose of arsenic for several months. We discovered that a five month continuous exposure of breast epithelial cells to arsenic results in increased cell proliferation, increased wound healing, increased anchorage independent growth, as well as increased matrigel invasion. These studies suggest arsenic induces tumorigenic transformation of breast epithelial cells. Our preliminary studies revealed that mitochondria are important targets of arsenic induced transformation. Mitochondria control cell growth and cell death. Mitochondria perform other cellular functions including ATP production via mitochondrial oxidative phosphorylation (mtOXPHOS). We discovered that exposure to arsenic induces selective subgenomic amplification of chromosome 5p which contains many genes involved in mitochondrial function. Consistent with this finding arsenic-transformed cells show 1) increased Complex I and IV activities;2) an increased expression of Complex I regulatory subunits NDUFA13 or GRIM19 (gene associated with retinoid interferon induced mortality) and non-regulatory NDUFB8 comprising the mtOXPHOS;and 3) increased expression of COXII subunit comprising complex IV. Furthermore our study suggest that arsenic-treatment did not 1) induce changes in Complex II and III activities and 2) alter the expression of arsenic-transporters. However, arsenic-transformed cells produce an increased level of reactive oxygen species. We hypothesize that arsenic disrupts mtOXPHOS function which contributes to tumorigenic transformation of breast epithelial cells. To address the proposed hypothesis, we plan to:
Aim 1 : Determine the spectrum of arsenic-induced mtOXPHOS dysfunction during progression (1, 2, 3, 4 months) to tumorigenic transformation (5 months) of mammary epithelial cells.
Aim 2 : Determine arsenic-induced changes affecting subunit gene expression, composition and organization of mtOXPHOS super-complexes during the progression and tumorigenic transformation of mammary epithelial cells.
Aim 3 : Determine a role for a regulatory and a non-regulatory subunit of mtOXPHOS Complex I in resistance to arsenic-induced cell death and tumor development. NDUFA13/GRIM19 encodes the regulatory component of mtOXPHOS Complex I and is essential for the assembly and enzymatic activity of Complex I. In contrast, NDUFB8 encodes a non- regulatory accessory subunit that is not involved in the catalysis of Complex I. The proposed studies should provide insight into the mechanism(s) involved in arsenic induced breast cancer and in the future may help prevent or treat breast cancers in female veterans.
Since a significant number of women serve in the military an increasing number of female veterans are impacted by breast cancer. Understanding the mechanisms involved in breast cancer will have broad and significant relevance to the health missions of the VA and may help develop new agents that can be used to prevent and treat breast cancers in female veterans.
|Singh, Bhupendra; Schoeb, Trenton R; Bajpai, Prachi et al. (2018) Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. Cell Death Dis 9:735|
|Koo, Dal-Hoe; Singh, Bhupendra; Jiang, Jiming et al. (2018) Single molecule mtDNA fiber FISH for analyzing numtogenesis. Anal Biochem 552:45-49|
|Choudhury, Aaheli Roy; Singh, Keshav K (2017) Mitochondrial determinants of cancer health disparities. Semin Cancer Biol 47:125-146|
|Singh, Keshav K; Choudhury, Aaheli Roy; Tiwari, Hemant K (2017) Numtogenesis as a mechanism for development of cancer. Semin Cancer Biol 47:101-109|
|Singh, Bhupendra; Modica-Napolitano, Josephine S; Singh, Keshav K (2017) Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome. Semin Cancer Biol 47:1-17|
|Carden, Trevor; Singh, Bhupendra; Mooga, Ved et al. (2017) Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression. J Biol Chem 292:20694-20706|
|Nunes, Joana B; Peixoto, Joana; Soares, Paula et al. (2015) OXPHOS dysfunction regulates integrin-?1 modifications and enhances cell motility and migration. Hum Mol Genet 24:1977-90|
|Singh, Bhupendra; Owens, Kjerstin M; Bajpai, Prachi et al. (2015) Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties. PLoS One 10:e0139846|
|Zhang, Hengshan; Singh, Keshav K (2014) Global genetic determinants of mitochondrial DNA copy number. PLoS One 9:e105242|
|Donthamsetty, Shashikiran; Brahmbhatt, Meera; Pannu, Vaishali et al. (2014) Mitochondrial genome regulates mitotic fidelity by maintaining centrosomal homeostasis. Cell Cycle 13:2056-63|