t-DARPP regulates phosphatidylinositol-3-kinase-dependent cell growth in breast cancer.

Vangamudi B, Peng DF, Cai Q, El-Rifai W, Zheng W, Belkhiri A
Mol Cancer. 2010 9: 240

PMID: 20836878 · PMCID: PMC2945963 · DOI:10.1186/1476-4598-9-240

BACKGROUND - Recent reports have shown that t-DARPP (truncated isoform of DARPP-32) can mediate trastuzumab resistance in breast cancer cell models. In this study, we evaluated expression of t-DARPP in human primary breast tumors, and investigated the role of t-DARPP in regulating growth and proliferation in breast cancer cells.

RESULTS - Quantitative real time RT-PCR analysis using primers specific for t-DARPP demonstrated overexpression of t-DARPP in 36% of breast cancers (13/36) as opposed to absent to very low t-DARPP expression in normal breast tissue (p < 0.05). The mRNA overexpression of t-DARPP was overwhelmingly observed in ductal carcinomas, including invasive ductal carcinomas and intraductal carcinomas, rather than other types of breast cancers. The immunohistochemistry analysis of DARPP-32/t-DARPP protein(s) expression in breast cancer tissue microarray that contained 59 tumors and matched normal tissues when available indicated overexpression in 35.5% of primary breast tumors that were more frequent in invasive ductal carcinomas (43.7%; 21/48). In vitro studies showed that stable overexpression of t-DARPP in MCF-7 cells positively regulated proliferation and anchorage-dependent and -independent growth. Furthermore, this effect was concomitant with induction of phosphorylation of AKT(ser473) and its downstream target phospho(ser9) GSK3β, and increased Cyclin D1 and C-Myc protein levels. The knockdown of endogenous t-DARPP in HCC1569 cells led to a marked decrease in phosphorylation of AKTs(ser473) and GSK3β(ser9). The use of PI3K inhibitor LY294002 or Akt siRNA abrogated the t-DARPP-mediated phosphorylation of AKT(ser473) and led to a significant reduction in cell growth.

CONCLUSIONS - Our findings underscore the potential role of t-DARPP in regulating cell growth and proliferation through PI3 kinase-dependent mechanism.

MeSH Terms (19)

Breast Neoplasms Cell Line, Tumor Cell Proliferation Cell Survival Chromones Cyclin D1 Dopamine and cAMP-Regulated Phosphoprotein 32 Female Humans Immunoblotting Immunohistochemistry Morpholines Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Phosphorylation Polymerase Chain Reaction Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-myc RNA, Small Interfering

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