Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2 -associated hereditary breast cancer

Yanying Huo, Hong Cai, Irina Teplova, Christian Bowman-Colin, Guanghua Chen, Sandy Price, Nicola Barnard, Shridar Ganesan, Vassiliki Karantza, Eileen White, Bing Xia

Research output: Contribution to journalArticlepeer-review

108 Scopus citations


Hereditary breast cancers stem from germline mutations in susceptibility genes such as B RCA1, B RCA2, and P ALB2, 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. Significance: Our fi ndings directly show a tumor-promoting role of autophagy in a new model of hereditary breast cancer. Given the close functional relationship and the genetic similarity between PALB2 and BRCA1/2, our results further suggest that inhibition of autophagy may represent a new avenue to the prevention or treatment of a signifi cant portion of hereditary breast cancers, namely those associated with DNA damage and oxidative stress.

Original languageEnglish (US)
Pages (from-to)894-907
Number of pages14
JournalCancer Discovery
Issue number8
StatePublished - Aug 2013

All Science Journal Classification (ASJC) codes

  • Oncology


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