Identification of the Molecular Determinants of Breast Epithelial Cell Polarity
Final rept. 8 Sep 2003-7 Sep 2006
CALIFORNIA UNIV BERKELEY
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Maintenance of apico-basal polarity in normal breast epithelial acini requires a balance between cell proliferation and cell death and proper cell-cell and cell-extracelluar matrix signaling. Aberrant regulation of any of these processes can disrupt tissue architecture and initiate tumor formation. We found that the small GTPase Rap 1 is a crucial effector in the organization of acinar structure and the induction of lumen formation. Rapi activity in malignant HMT-3522 T4-2 cells is appreciably higher than in their non-malignant couterparts, S1. Expression of dominant-negative Rap 1 in T4-2 cells resulted in phenotypic reversion, that is, formation of acinar structures with correct apico-basal polarity, and dramatically reduced tumor incidence despite the persistence of genomic abnormalities. The Rap 1 revertants also featured prominent central lumena not observed when other reverting agents are used. Conversely, expression of dominant-active RapI in T4-2 cells inhibited phenotypic reversion and led to increased invasiveness. Thus, RapI acts as a central regulator of breast architecture, and instructs polarity during acinar morphogenesis.
- Anatomy and Physiology
- Medicine and Medical Research