Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis

Abstract

We investigated the role of protein tyrosine phosphatase 1B (PTP1B) in mammary tumorigenesis using both genetic and pharmacological approaches. It has been previously shown that transgenic mice with a deletion mutation in the region of Erbb2 encoding its extracellular domain (referred to as NDL2 mice, for 'Neu deletion in extracellular domain 2') develop mammary tumors that progress to lung metastasis. However, deletion of PTP1B activity in the NDL2 transgenic mice either by breeding with Ptpn1-deficient mice or by treatment with a specific PTP1B inhibitor results in significant mammary tumor latency and resistance to lung metastasis. In contrast, specific overexpression of PTP1B in the mammary gland leads to spontaneous breast cancer development. The regulation of ErbB2-induced mammary tumorigenesis by PTB1B occurs through the attenuation of both the MAP kinase (MAPK) and Akt pathways. This report provides a rationale for the development of PTP1B as a new therapeutic target in breast cancer.

Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

“…E: Representative Western blot analysis with the antibodies against PCNA, cyclins D1 and E, and ␤-actin as a loading control. recent articles 43,44 noted that the loss of PTP1B in mouse models of breast cancer is accompanied by attenuation of the Ras/ERK pathway. Thus, during hepatic regeneration, the overall effect of cytokines and growth factors is a coordinated response that is enhanced in the absence of PTP1B, resulting in accelerated and/or increased expression of cell cycle markers and the reexpression of IRA.…”

Protein-tyrosine Phosphatase 1B Antagonized Signaling by Insulin-like Growth Factor-1 Receptor and Kinase BRK/PTK6 in Ovarian Cancer Cells*

“…In contrast, PTP1B is highly expressed in some tumors, such as breast, and plays a positive role in signaling by the HER2 oncoprotein-tyrosine kinase. Although the mechanism is unclear and may involve dephosphorylation and activation of SRC (52) or activation of RAS-MAPK signaling via dephosphorylation of p62DOK (53), this raises the possibility that PTP1B may also be a therapeutic target for treatment of HER2-positive cancer (54). Nevertheless, consistent with the importance of context and specificity in PTP function, signaling through the EGF receptor, which is from the same family of PTKs as HER2, is not augmented by PTP1B; in fact, PTP1B is recognized for its inhibitory effects on EGFR signaling (23).…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Dephosphorylation has the capacity to down-regulate activated receptors through abolishment of binding sites for signaling intermediates and adaptor proteins. Although PTP1B can dephosphorylate ErbB receptors, its relative contribution to downregulation of ErbB receptors is questionable as PTP1B appears to promote oncogenesis in ErbB2-induced mammary tumorigenesis in mice, suggesting other targets for this phosphatase in regulating cell proliferation [82,83]. Internalization of activated receptors plays a central role in dampening signaling by targeting receptors for lysosomal degradation or in some cases promoting ligand dissociation (Fig.…”