PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization.
Tyrosine phosphorylation is tightly regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), and has a critical role in malignant transformation and progression. Although PTKs have a well-established role in regulating breast cancer growth, contribution of PTPs remains mostly unknown. Here, we report that the tyrosine phosphatase PTPH1 stimulates breast cancer growth through regulating vitamin D receptor (VDR) expression. PTPH1 was shown to be overexpressed in 49% of primary breast cancer and levels of its protein expression positively correlate with the clinic metastasis, suggesting its oncogenic activity. Indeed, PTPH1 promotes breast cancer growth by a mechanism independent of its phosphatase activity, but dependent of its stimulatory effect on the nuclear receptor VDR protein expression and depletion of induced VDR abolishes the PTPH1 oncogenic activity. Additional analyses showed that PTPH1 binds VDR and increases its cytoplasmic accumulation, leading to their mutual stabilization and stable expression of a nuclear localization-deficient VDR abolishes the growth-inhibitory activity of the receptor independent of 1,25-dihydroxyvitamin D3. These results reveal a new paradigm in which a PTP may stimulate breast cancer growth through increasing cytoplasmic translocation of a nuclear receptor, leading to their mutual stabilization.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002117:Calcitriol / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000556:secondary*; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000556:secondary*; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D011485:Protein Binding; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3 / Q000096:biosynthesis* / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018167:Receptors, Calcitriol; C516656:PTPN3 protein, human; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3; D002117:Calcitriol