Protein interacting with C α kinase 1 (PICK1) is involved in promoting tumor growth and correlates with poor prognosis of human breast cancer

Abstract

Protein interacting with C a kinase 1 (PICK1), which interacts with multiple different proteins in a variety of cellular contexts, is believed to play important roles in diverse pathological conditions including cancer. In this study, we attempted to investigate the correlation of PICK1 with clinicopathological features as well as prognosis of human breast cancer. In addition, we aimed at a better understanding of the biological function of PICK1 in breast cancer cell biology. As judged by semi-quantitative RT-PCR and western blotting, PICK1 was overexpressed in tumor cells as compared to adjacent normal epithelia in breast, lung, gastric, colorectal, and ovarian cancer. As judged by immunostaining breast cancer tissue microarrays, high levels of PICK1 expression correlated with shortened span of overall survival (OS). Protein interacting with C a kinase 1 (PICK1) expression seemed to be specifically associated with reduced OS in lymph node-positive, Her ⁄ neu-2 positive, and the basal-like type subgroups, respectively. Consistently, the expression of PICK1 correlated with histological grade, lymph node metastasis, Her-2 ⁄ neu-positivity, and triple-negative basal-like breast cancer. Protein interacting with C a kinase 1 (PICK1) was not correlated with menopausal status, tumor size, or hormone receptor status. In a complementary study, transfection of MDA-MB-231 cells with PICK1 siRNA decreased cell proliferation and colony formation in vitro and inhibited tumorigenicity in nude mice. Our clinical and experimental evidence supports an oncogenic role of PICK1 in human breast cancer. In particular, our data suggest that PICK1 promotes tumor cell proliferation. Taken together, PICK1 may serve not only as a marker for poor prognosis, but also as a therapeutic target in breast cancer. (Cancer Sci 2010; 101: 1536-1542 B reast cancer is one of the leading causes of cancer death among women worldwide.(1) The incidence and mortality rate of breast cancer have increased sharply in China over the past few decades, (2) whereas the breast cancer mortality rate in developed countries has declined in the same period, likely due to the implementation of screening, (3) improvements in early breast cancer management, (4) and improved systemic adjuvant treatments.(5) Currently, the strategy for breast cancer management is primarily based on the traditional prognostic and predictive factors including histologic, clinical, and some well-defined molecular profiles. Since the biomarker profile may provide valuable insights into the underlying mechanisms of disease progression, (6,7) in light of the well-documented racial disparities in breast cancer incidence and prognosis, it is important to identify and validate specific biomarkers for Chinese breast cancer patients.Protein interacting with C a kinase 1 (PICK1), a PSD95 ⁄ disklarge ⁄ ZO-1 (PDZ) domain-containing protein, was originally identified by a yeast two-hybrid system on the basis of its interaction with protein kinase C a (PKCa). (8,9) In addition to PKCa,PICK1 also interac...

PICK1 promotes caveolin-dependent degradation of TGF-β type I receptor

“…Increased expression of PICK1 was reported in breast cancer [26]. We observed a negative correlation between PICK1 and p-Smad2 levels in breast cancer samples, indicating that PICK1 may promote breast cancer formation by restricting TGF-β signaling.…”

“…It has been reported that PICK1 is highly expressed in breast cancer cells [26]. To investigate whether the negative regulation of PICK1 on TGF-β signaling contributes to breast cancer development, we first examined the effect of PICK1 on the antiproliferative activity of TGF-β in breast epithelial MCF10A cells.…”

“…Its potential effects on signal transduction and related diseases remain unclear. Recent evidences suggest that PICK1 may affect human cancer development [18,[24][25][26], in which TGF-β signaling has been reported to play significant roles [5].…”

PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway

“…43 Very recently it was shown that PICK, a critical mediator of AMPAR trafficking in neuronal synapses, is overexpressed in breast cancer and antagonizes TGF-β1 signaling by promoting caveolin-dependent degradation of TβRI, thus abolishing TGF-β1-induced growth inhibition. 44,45 However, it was also reported that TβRI is a target of homeoprotein Six1 and Six1-induced upregulation of TβRI is required to switch of TGF-βI signaling to the prometastatic phenotype, such as EMT. 46 Although our study reveals that modulation of either TβRI or TβRII by PPARδ-ABCA1-Cav1 signaling provokes similar effect in prostate carcinoma cells, further studies are required to clarify whether TβRI and TβRII have differential functions in the shift of TGF-βI signaling depending on cellular context and origins.…”

Expression of Elongation Factor (EF)-Tu Is Correlated with Prognosis of Gastric Adenocarcinomas

“…Gastric adenocarcinoma encompasses many subtypes with distinct genetic and biological features. Identification of new biological markers to determine the risk of poor prognosis is important for designing treatment strategies [2,3]. …”