Alcohol and cancer: dietary alcohol enhances tissue overgrowth upon loss of Hippo Pathway signaling. Cathie M. Pfleger¹, Anoj Ilanges^1,2, Maryam Jahanshahi¹. 1) Dept Oncological Sci, Mount Sinai Sch Med, New York, NY; 2) Yale University, New Haven, CT.

   Alcohol consumption is a significant risk factor in cancers of organs that contact alcohol and in the liver where alcohol is metabolized. Interestingly, a link is also reported in breast cancer. Despite strong epidemiological links, the role of alcohol in cancer is not understood. Drosophila models have been established to explore the role of alcohol in other disease contexts including models of fetal alcohol syndrome and alcohol addiction. Drosophila can also model cancer-relevant phenotypes such as tissue overgrowth, making it an ideal system to elucidate the relationship between alcohol and cancer. We report here that screening Drosophila overgrowth models for response to dietary ethanol identified interactions with the Hippo tumor suppressor. The Hippo Pathway is a bona-fide tumor suppressor pathway highly conserved from flies to mammals that acts as a master regulatory pathway to restrict growth and proliferation and to promote apoptosis. Of note, loss of Hippo signaling is implicated in a range of cancers that overlaps strikingly with the spectrum of alcohol-mediated cancers including digestive tract, liver, and breast cancers. A host of upstream factors activate the core cassette of Hippo signaling via Hippo (Hpo). Activated Hpo kinase phosphorylates and activates downstream kinase Warts (Wts). Wts phosphorylates and inhibits transcriptional co-activator Yorkie (Yki), a potent oncogene. We report that in multiple tissues, including the eye and wing, alcohol enhanced tissue overgrowth upon loss of multiple Hippo Pathway tumor suppressor components. Surprisingly, alcohol did not enhance overgrowth due to over-expressing Yki. Consistent with this, mammalian cells exposed to alcohol showed phosphorylation of Wts homolog Lats1 but not of the Yki homolog YAP. Our studies reveal a novel, highly conserved interaction between alcohol and the Hippo Pathway and may implicate a YAP-independent role for Hippo Pathway tumor suppression in alcohol-mediated cancers.