Rap1 integrates tissue polarity, lumen formation, and tumorigenic potential in human breast epithelial cells.
Maintenance of apico-basal polarity in normal breast epithelial acini requires a balance between cell proliferation, cell death, and proper cell-cell and cell-extracellular matrix signaling. Aberrations in any of these processes can disrupt tissue architecture and initiate tumor formation. Here, we show that the small GTPase Rap1 is a crucial element in organizing acinar structure and inducing lumen formation. Rap1 activity in malignant HMT-3522 T4-2 cells is appreciably higher than in S1 cells, their nonmalignant counterparts. Expression of dominant-negative Rap1 resulted in phenotypic reversion of T4-2 cells, led to the formation of acinar structures with correct polarity, and dramatically reduced tumor incidence despite the persistence of genomic abnormalities and baseline growth. The resulting acini contained prominent central lumina not observed when other reverting agents were used. Conversely, expression of dominant-active Rap1 in T4-2 cells inhibited phenotypic reversion and led to increased invasiveness and tumorigenicity. Thus, Rap1 acts as a central regulator of breast architecture, with normal levels of activation instructing polarity during acinar morphogenesis, and increased activation inducing tumor formation and progression to malignancy.
Itoh
Masahiko
M
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. mitoh@dokkyomed.ac.jp
Nelson
Celeste M
CM
Myers
Connie A
CA
Bissell
Mina J
MJ
D001940:Breast / Q000201:enzymology* / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D016764:Cell Polarity / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins