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Proteomes 2018, 6(2), 16; https://doi.org/10.3390/proteomes6020016

Proteomics Analysis to Assess the Role of Mitochondria in BRCA1-Mediated Breast Tumorigenesis

1
Laboratory of Proteomics, Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Catanzaro 88100, Italy
2
Stem Cell Laboratory, Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro 88100, Italy
3
Laboratory of Molecular Oncology, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy
4
CIS for Genomics and Molecular Pathology, Magna Graecia University of Catanzaro, Catanzaro 88100, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 16 March 2018 / Revised: 22 March 2018 / Accepted: 23 March 2018 / Published: 27 March 2018
(This article belongs to the Special Issue Proteomic Biomarkers in Human Diseases)
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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. View Full-Text
Keywords: mitochondria; HIF-1α; 2D-DIGE; breast cancer; BRCA1 mitochondria; HIF-1α; 2D-DIGE; breast cancer; BRCA1
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Concolino, A.; Olivo, E.; Tammè, L.; Fiumara, C.V.; De Angelis, M.T.; Quaresima, B.; Agosti, V.; Costanzo, F.S.; Cuda, G.; Scumaci, D. Proteomics Analysis to Assess the Role of Mitochondria in BRCA1-Mediated Breast Tumorigenesis. Proteomes 2018, 6, 16.

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