title: Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer.
abstract: Hereditary breast cancers stem from germline mutations in susceptibility genes such as BRCA1, BRCA2, and PALB2, whose products function in the DNA damage response and redox regulation. Autophagy is an intracellular waste disposal and stress mitigation mechanism important for alleviating oxidative stress and DNA damage response activation; it can either suppress or promote cancer, but its role in breast cancer is unknown. Here, we show that similar to Brca1 and Brca2, ablation of Palb2 in the mouse mammary gland resulted in tumor development with long latency, and the tumors harbored mutations in Trp53. Interestingly, impaired autophagy, due to monoallelic loss of the essential autophagy gene Becn1, reduced Palb2-associated mammary tumorigenesis in a Trp53-wild-type but not conditionally null background. These results indicate that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, p53 is a barrier to cancer development, whereas autophagy facilitates cell survival and tumorigenesis.
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors: Yanying
authors: Y
authors: Huo
authors: Hong
authors: H
authors: Cai
authors: Irina
authors: I
authors: Teplova
authors: Christian
authors: C
authors: Bowman-Colin
authors: Guanghua
authors: G
authors: Chen
authors: Sandy
authors: S
authors: Price
authors: Nicola
authors: N
authors: Barnard
authors: Shridar
authors: S
authors: Ganesan
authors: Vassiliki
authors: V
authors: Karantza
authors: Eileen
authors: E
authors: White
authors: Bing
authors: B
authors: Xia
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001343:Autophagy; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D000071186:Beclin-1; D063646:Carcinogenesis; D016922:Cellular Senescence; D004249:DNA Damage; D004195:Disease Models, Animal; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D006579:Heterozygote; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D000076164:Fanconi Anemia Complementation Group N Protein; C552932:Palb2 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
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