AND-34 activates phosphatidylinositol 3-kinase and induces anti-estrogen resistance in a SH2 and GDP exchange factor-like domain-dependent manner

Kyriacos H. Felekkis, Radha P. Narsimhan, Richard Near, Ariel F. Castro, Yi Zheng, Lawrence Quilliam, Adam Lerner

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

AND-34, a 95-kDa protein with modest homology to Ras GDP exchange factors, associates with the focal adhesion protein p130Cas. Overexpression of AND-34 confers anti-estrogen resistance in breast cancer cell lines, a property linked to its ability to activate Rac. Here, we show that both the GDP exchange factor-like domain and the SH2 domain of AND-34 are required for Rac activation and for resistance to the estrogen receptor (ER) antagonist ICI 182,780. As phosphatidylinositol 3-kinase (PI3K) signaling can regulate Rac activation, we examined the effects of AND-34 on PI3K. Overexpression of AND-34 in MCF-7 cells increased PI3K activity and augmented Akt Ser473 phosphorylation and kinase activity. Inhibition of PI3K with LY294002 or a dominant-negative p85 construct blocked AND-34-mediated Rac and Akt activation. Although R-Ras can activate PI3K, transfection with constitutively active R-Ras failed to induce Rac activation and AND-34 overexpression failed to induce R-Ras activation. Treatment of either vector-only or AND-34-transfected ZR-75-1 cells with ICI 182,780 markedly diminished ERα levels, suggesting that AND-34-induced anti-estrogen resistance is likely to occur by an ERα-independent mechanism. Treatment of a ZR-75-1 breast cancer cell line stably transfected with AND-34 plus 2 μmol/L LY294002 or 10 μmol/L NSC23766, a Rac-specific inhibitor, abrogated AND-34-induced resistance to ICI 182,780. Our studies suggest that AND-34-mediated PI3K activation induces Rac activation and anti-estrogen resistance in human breast cancer cell lines.

Original languageEnglish
Pages (from-to)32-41
Number of pages10
JournalMolecular Cancer Research
Volume3
Issue number1
StatePublished - Jan 2005

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Phosphatidylinositol 3-Kinase
Guanine Nucleotide Exchange Factors
Estrogens
Breast Neoplasms
Cell Line
Estrogen Receptors
Crk-Associated Substrate Protein
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Focal Adhesions
src Homology Domains
MCF-7 Cells
Transfection
Phosphotransferases
Phosphorylation
fulvestrant

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

AND-34 activates phosphatidylinositol 3-kinase and induces anti-estrogen resistance in a SH2 and GDP exchange factor-like domain-dependent manner. / Felekkis, Kyriacos H.; Narsimhan, Radha P.; Near, Richard; Castro, Ariel F.; Zheng, Yi; Quilliam, Lawrence; Lerner, Adam.

In: Molecular Cancer Research, Vol. 3, No. 1, 01.2005, p. 32-41.

Research output: Contribution to journalArticle

Felekkis, Kyriacos H. ; Narsimhan, Radha P. ; Near, Richard ; Castro, Ariel F. ; Zheng, Yi ; Quilliam, Lawrence ; Lerner, Adam. / AND-34 activates phosphatidylinositol 3-kinase and induces anti-estrogen resistance in a SH2 and GDP exchange factor-like domain-dependent manner. In: Molecular Cancer Research. 2005 ; Vol. 3, No. 1. pp. 32-41.
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