Molecular Dissection of Tumor Invasion

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DESCRIPTION (provided by applicant): Cell invasion and metastasis mark the most lethal phase of cancer, but little is known about the key molecular events that initiate this crucial turning point. Our systematic genetic analysis in Drosophila has revealed that basolateral junction proteins, which are highly conserved and precisely localized at specific sites of intercellular contact in both animals and man, act as key invasion suppressors. They control both epithelial architecture and prevent dissemination of epithelial tumor cells. The basolateral junction is comprised of Immunoglobulin superfamily members Fasciclin2 (human NCAM) and Neuroglian (human L1), and scaffolding molecules Discslarge (hDIg) and Lethal Giant larvae (hLgl). We have identified the first pathway that acts down stream of the basolateral junction that suppresses epithelial invasion. Three genes encoding signaling molecules, Warts (human Lats1/2), Mats (human Mobla), and Yorki (human Yap), are all implicated in human carcinogenesis. Our data is the first evidence that they are in a basolateral junction pathway crucial for suppressing tumor invasion. A key target of this pathway is Drosophila Amplified in Breast Cancer-1 (DAIB1), which in humans is a steroid transcriptional co- activator that acts as an oncogene. AIB1 is involved in resistance to breast cancer therapeutic tamoxifen, but little is known about control of AIB1 expression. Our data indicate that basolateral junction signals and DAIB1 are in a positive feedback loop. Further, we find that AIB1 is over expressed in greater than 90% of human ovarian cancers, and that Lats2 and Yap are lost in 60% of breast cancers, specifically at the transition to invasion. Our specific aims are to: (1) Order the pathway by which the basolateral junction signals through Wts and Mats (Lats and Mobla) to activate DAIB1 (AIB1) expression in the nucleus, (2) Establish the molecular mechanisms by which the basolateral junction signals to AIB1/DAIB1, and (3) Establish the importance of the basolateral junction signaling pathway for suppressing human tumor cell invasion. These aims will delineate the first pathway by which basolateral junctions control epithelial invasiveness, which may provide important tools for diagnosis and treatment of invasive cancers.