title: Pro-tumorigenic function of autophagy in mammary oncogenesis.
abstract: Autophagy is a highly conserved catabolic cellular process by which cells degrade intracellular constituents in lysosomes, and its dysfunctions have been associated with a variety of human diseases including cancer. Previous studies have linked autophagy to both tumor-suppressive and promoting functions in different contexts, although the pro-tumorigenic function of autophagy has not been examined directly in breast or other cancers in animal models with intact immune functions in vivo. FIP200 (focal adhesion kinase family interacting protein of 200 kD) is a component of the ULK1-Atg13-FIP200-Atg101 complex that is essential for the induction of mammalian autophagy. In our recent study, we show that conditional knockout (KO) of FIP200 in the well-characterized MMTV-PyMT mouse model of human breast cancer significantly suppresses mammary tumorigenesis and progression. Similar to a number of recent studies in Ras-transformed cells, our studies revealed the importance of autophagy in promoting tumorigenesis through regulation of tumor cell glycolysis and proliferation. In addition to the intrinsic defects in proliferation of FIP200-null tumor cells, we also showed that FIP200 deletion in mammary tumor cells triggers increased host anti-tumor immune surveillance, which also contributes to the decreased mammary tumorigenesis and progression. Our study provides the first direct demonstration of a pro-tumorigenic role of autophagy in oncogene-driven tumor models with intact immune functions in vivo. They also suggest FIP200 and other autophagy proteins as potential therapeutic targets for cancer treatment, and raise a number of questions for future studies on the potentially dual functions of autophagy in promoting and suppressing tumorigenesis under different conditions in vivo.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Huijun
authors.initials: H
authors.lastname: Wei
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; C428743:Rb1cc1 protein, mouse; D018631:ras Proteins; D000071193:Autophagy-Related Protein 7
references.citation: Genes Dev. 2011 Jul 15;25(14):1510-27
references.pmid: 21764854