Dysregulation of Mitochondrial Translation Caused by CBFB Deficiency Cooperates with Mutant PIK3CA and Is a Vulnerability in Breast Cancer.

Autor:	Malik N; Cancer and Stem Cell Epigenetics Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Kim YI; Cancer and Stem Cell Epigenetics Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Yan H; Cancer and Stem Cell Epigenetics Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Tseng YC; Cancer and Stem Cell Epigenetics Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., du Bois W; Animal Model and Genotyping Facility, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Ayaz G; Cancer and Stem Cell Epigenetics Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Tran AD; CCR Microscopy Core Facility, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Vera-Ramirez L; Metastasis Susceptibility Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.; Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology (Pfizer-University of Granada and Andalusian Regional Government), PTS, Granada, Spain.; Department of Physiology, Institute of Nutrition and Food Technology 'José Mataix Verdú,' Biomedical Research Center, University of Granada, Granada, Spain., Yang H; High-dimension Data Analysis Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Michalowski AM; Cancer and Stem Cell Epigenetics Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Kruhlak M; CCR Microscopy Core Facility, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Lee M; High-dimension Data Analysis Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Hunter KW; Metastasis Susceptibility Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Huang J; Cancer and Stem Cell Epigenetics Group, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2023 Apr 14; Vol. 83 (8), pp. 1280-1298.
DOI:	10.1158/0008-5472.CAN-22-2525
Abstrakt:	Understanding functional interactions between cancer mutations is an attractive strategy for discovering unappreciated cancer pathways and developing new combination therapies to improve personalized treatment. However, distinguishing driver gene pairs from passenger pairs remains challenging. Here, we designed an integrated omics approach to identify driver gene pairs by leveraging genetic interaction analyses of top mutated breast cancer genes and the proteomics interactome data of their encoded proteins. This approach identified that PIK3CA oncogenic gain-of-function (GOF) and CBFB loss-of-function (LOF) mutations cooperate to promote breast tumor progression in both mice and humans. The transcription factor CBFB localized to mitochondria and moonlighted in translating the mitochondrial genome. Mechanistically, CBFB enhanced the binding of mitochondrial mRNAs to TUFM, a mitochondrial translation elongation factor. Independent of mutant PI3K, mitochondrial translation defects caused by CBFB LOF led to multiple metabolic reprogramming events, including defective oxidative phosphorylation, the Warburg effect, and autophagy/mitophagy addiction. Furthermore, autophagy and PI3K inhibitors synergistically killed breast cancer cells and impaired the growth of breast tumors, including patient-derived xenografts carrying CBFB LOF and PIK3CA GOF mutations. Thus, our study offers mechanistic insights into the functional interaction between mutant PI3K and mitochondrial translation dysregulation in breast cancer progression and provides a strong preclinical rationale for combining autophagy and PI3K inhibitors in precision medicine for breast cancer. Significance: CBFB-regulated mitochondrial translation is a regulatory step in breast cancer metabolism and synergizes with mutant PI3K in breast cancer progression. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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