title: Distinct roles for Rho versus Rac/Cdc42 GTPases downstream of Vav2 in regulating mammary epithelial acinar architecture.
abstract: Non-malignant mammary epithelial cells (MECs) undergo acinar morphogenesis in three-dimensional Matrigel culture, a trait that is lost upon oncogenic transformation. Rho GTPases are thought to play important roles in regulating epithelial cell-cell junctions, but their contributions to acinar morphogenesis remain unclear. Here we report that the activity of Rho GTPases is down-regulated in non-malignant MECs in three-dimensional culture with particular suppression of Rac1 and Cdc42. Inducible expression of a constitutively active form of Vav2, a Rho GTPase guanine nucleotide exchange factor activated by receptor tyrosine kinases, in three-dimensional MEC culture activated Rac1 and Cdc42; Vav2 induction from early stages of culture impaired acinar morphogenesis, and induction in preformed acini disrupted the pre-established acinar architecture and led to cellular outgrowths. Knockdown studies demonstrated that Rac1 and Cdc42 mediate the constitutively active Vav2 phenotype, whereas in contrast, RhoA knockdown intensified the Vav2-induced disruption of acini, leading to more aggressive cell outgrowth and branching morphogenesis. These results indicate that RhoA plays an antagonistic role to Rac1/Cdc42 in the control of mammary epithelial acinar morphogenesis.
authors.affiliation: Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. lei_duan@rush.edu
authors.forename: Lei
authors.initials: L
authors.lastname: Duan
authors.forename: Gengsheng
authors.initials: G
authors.lastname: Chen
authors.forename: Sumeet
authors.initials: S
authors.lastname: Virmani
authors.forename: GuoGuang
authors.initials: G
authors.lastname: Ying
authors.forename: Srikumar M
authors.initials: SM
authors.lastname: Raja
authors.forename: Byung Min
authors.initials: BM
authors.lastname: Chung
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rainey
authors.forename: Manjari
authors.initials: M
authors.lastname: Dimri
authors.forename: Cesar F
authors.initials: CF
authors.lastname: Ortega-Cava
authors.forename: Xiangshan
authors.initials: X
authors.lastname: Zhao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Clubb
authors.forename: Chun
authors.initials: C
authors.lastname: Tu
authors.forename: Alagarsamy L
authors.initials: AL
authors.lastname: Reddi
authors.forename: Mayumi
authors.initials: M
authors.lastname: Naramura
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
mesh_terms: D002461:Cell Line, Transformed; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000254:growth & development*; D009024:Morphogenesis / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051567:Proto-Oncogene Proteins c-vav; C107953:RAC1 protein, human; C093651:VAV2 protein, human; C066737:RHOA protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein