Accession Number : ADA500910


Title :   Human Mammary Epithelial Cell Transformation by Rho GTPase through a Novel Mechanism


Descriptive Note : Final rept. 30 Jan 2005-28 Jul 2008


Corporate Author : NEBRASKA UNIV MEDICAL CENTER OMAHA


Personal Author(s) : Band, Vimia


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a500910.pdf


Report Date : Aug 2008


Pagination or Media Count : 46


Abstract : Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably utilized immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human epithelial cells (hMECs). We demonstrate here, that ectopic expression of wild-type RhoA as well as a constitutively-active RhoA mutant (G14V) in two independent primary hMEC strains led to their immortalization and preneoplastic transformation. These cells have continued to grow over 300 population doublings with no signs of senescence, whereas cells expressing the vector or dominant-negative RhoA mutant (T19N) senesced after 20 population doublings. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well known Rho-effectors including Rho-kinase, PKN and mDia 1 and 2, was also capable of immortalizing hMECs. Notably, similar to parental normal cells, Rho-immortalized cells have wild-type p53 and intact G1 cell cycle arrest upon adriamycin treatment. Rho-immortalized cells were anchorage-dependent. Lastly, microarray expression profiling of Rho-immortalized vs. parental cells showed altered expression of several genes previously implicated in immortalization and breast cancer progression. Taken together, these results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked cellular transformation and breast cancer.


Descriptors :   *CELLS(BIOLOGY) , *BREAST CANCER , HUMANS , MOLECULES , AGING(PHYSIOLOGY) , GENES , LINKAGES , TRANSFORMATIONS , CHEMOTHERAPEUTIC AGENTS , EPITHELIUM , FUNCTIONS , SIGNS AND SYMPTOMS


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE