AND-34/BCAR3, a GDP Exchange Factor Whose Overexpression Confers Antiestrogen Resistance, Activates Rac, PAK1, and the Cyclin D1 Promoter

Dongpo Cai, Anita Iyer, Kyriacos N. Felekkis, Richard I. Near, Zhijun Luo, Jonathan Chernoff, Chris Albanese, Richard G. Pestell, Adam Lerner

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

AND-34 is a murine protein that binds by a cdc25-like GDP exchange factor domain to the focal adhesion docking protein p130Cas. Overexpression of either of the human homologues of AND-34 and p130Cas, BCAR3 and BCAR1, respectively, has been reported to induce resistance to antiestrogens in breast cancer cell lines. Here we show that overexpression of AND-34 leads to activation of the Rho family GTPases Cdc42 and Rac. Consistent with these findings, BCAR3 overexpression induced alterations in F-actin distribution and augmented both autophosphorylation and kinase activity of the Cdc42/Rac-responsive serine/threonine kinase PAK1. p130Cas-associated BCAR3 protein was detected in the estrogen-independent breast cancer cell line 578-T, but not in estrogen-dependent MCF7 or ZR-75-1 cells. Stable ZR-75-1 transfectants overexpressing BCAR3, but not vector-only transfectants, grew in the presence of the pure antiestrogen ICI 182,780. Stable transfection with RacV12, a constitutively active form of Rac1, also induced antiestrogen resistance in ZR-75-1 cells. Transient transfection of BCAR3 in estrogen-dependent MCF7 cells induced activation of luciferase constructs containing the proximal 1745 or 163 bp but not 66 bp of the cyclin D1 promoter. Such cyclin D1 promoter activation was inhibited by dominant negative forms of Rac1 and PAK1. Overexpression of the PAK1 autoinhibitory domain (residues 83-149) but not an inactive PAK1 autoinhibitory domain point mutant (L107F) also blocked BCAR3-mediated cyclin D1 activation. These studies suggest that AND-34/BCAR3 induces antiestrogen resistance in breast cancer cell lines by a Rac1- and PAK1-dependent pathway.

Original languageEnglish
Pages (from-to)6802-6808
Number of pages7
JournalCancer Research
Volume63
Issue number20
Publication statusPublished - 15 Oct 2003

Fingerprint

Dive into the research topics of 'AND-34/BCAR3, a GDP Exchange Factor Whose Overexpression Confers Antiestrogen Resistance, Activates Rac, PAK1, and the Cyclin D1 Promoter'. Together they form a unique fingerprint.

Cite this