Abstract
Mitochondria are the organelles deputed to energy production, but they are also involved in carcinogenesis, cancer progression, and metastasis, playing a role in altered energy metabolism in cancer cells. Mitochondrial metabolism is connected with several mitochondrial pathways such as ROS signaling, Ca2+ homeostasis, mitophagy, and mitochondrial biogenesis. These pathways are merged in an interactive super-network that seems to play a crucial role in cancer. Germline mutations of the BRCA1 gene account for 5–10% of breast cancers and confer a risk of developing the disease 10- to 20-fold much higher than in non-carriers. By considering metabolic networks that could reconcile both genetic and non-genetic causal mechanisms in BRCA1 driven tumorigenesis, we herein based our study on the hypothesis that BRCA1 haploinsufficiency might drive metabolic rewiring in breast epithelial cells, acting as a push toward malignant transformation. Using 2D-DIGE we analyzed and compared the mitochondrial proteomic profile of sporadic breast cancer cell line (MCF7) and BRCA1 mutated breast cancer cell line (HCC1937). Image analysis was carried out with Decider Software, and proteins differentially expressed were identified by LC-MS/MS on a quadrupole-orbitrap mass spectrometer Q-Exactive. Ingenuity pathways analysis software was used to analyze the fifty-three mitochondrial proteins whose expression resulted significantly altered in response to BRCA1 mutation status. Mitochondrial Dysfunction and oxidative phosphorylation, and energy production and nucleic acid metabolism were, respectively, the canonical pathway and the molecular function mainly affected. Western blotting analysis was done to validate the expression and the peculiar mitochondrial compartmentalization of specific proteins such us HSP60 and HIF-1α. Particularly intriguing is the correlation between BRCA1 mutation status and HIF-1α localization into the mitochondria in a BRCA1 dependent manner. Data obtained led us to hypothesize an interesting connection between BRCA1 and mitochondria pathways, capable to trigger metabolic changes, which, in turn, sustain the high energetic and anabolic requirements of the malignant phenotype.
Highlights
Worldwide, breast cancer (BC) is the most commonly diagnosed cancer type and represents the leading cause of cancer death among women
The main finding of this paper is that endogenous Hypoxia inducible factor-1α (HIF-1α) might localize with mitochondrial fractions in response to BRCA1 mutated status
HIF-1α is best known as a key regulator component of hypoxia response, we hypothesize that HIF-1α may have additional functions outside the nucleus
Summary
Breast cancer (BC) is the most commonly diagnosed cancer type and represents the leading cause of cancer death among women. It is genetically and morphologically highly heterogeneous and subgrouping relying on pathological and clinical data can only partially reflect the clinical diversity of the disease. Breast cancer is associated with somatic mutations in breast cells acquired during a women’s lifetime. 5–10 percent of all cases are hereditary breast cancer, and are associated with distinct mutations on specific genes such us BRCA1, BRCA2, PTEN and CHEK2. BRCA1 mutation carriers seem to have specific pathological features and gene expression profile [1,2]. BRCA1 is implicated in DNA double-strand break repair, transcriptional regulation, cell cycle control, apoptosis and resistance to chemotherapy [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
