Abstract 1061A: Role of protein tyrosine phosphatase PTPH1 in breast cancer

Abstract

Abstract Tyrosine phosphorylation, which is controlled by the balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), regulates critical cellular processes including proliferation and malignant transformation. While PTKs have a well-established role in breast cancer, the contribution of PTPs remains mostly unknown. Our recent studies demonstrated that the PTPH1 tyrosine phosphatase promotes K-Ras-dependent colon cancer growth through binding and dephosphorylating p38γ MAPK, and here we showed that PTPH1 increases breast cancer growth through the nuclear receptor VDR (vitamin D receptor). PTPH1 was shown to be over-expressed in about 50% of primary breast tumors and importantly its expression levels are significantly higher in HER-2 positive breast cancers. PTPH-forced expression increases breast cancer growth independent of its phosphatase activity and its oncogenic activity was further established by a growth inhibitory response through shRNA-mediated PTPH1 depletion. Mechanistically, PTPH1 was found to specifically induce the nuclear receptor VDR but not ER or PR expression and inhibition of endogenous VDR expression by shRNA or the genetic knockout completely blocks PTPH1-induced growth stimulation, which couples with an altered intracellular VDR localization. These results reveal a promoting role of a novel tyrosine phosphtase PTPH1 in breast cancer growth through signaling cross-talk with VDR, which may be a new target for breast cancer control. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1061A.