Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

Abstract

In this study, we show that proliferation of breast cancer cells is suppressed by IGF-1-activated JNK MAPK pathway. The molecular mechanism by which c-jun-NH,-kinase (JNK) activation induces antiproliferative signals in IGF-1-stimulated breast cancer cells remains unknown. Tyrosine phosphatase SHP1 is known to negatively regulate signal transduction pathways activated by cell surface receptors including IGF-1. Moreover, SHP1 transcript and protein levels are increased in epithelial tumors. Therefore, we hypothesized that IGF-activated JNK induces expression of SHP1 in breast cancer cells. To further clarify the role of SHP1 in tumor growth, we correlated the proliferation rates of breast adenocarcinoma cells with SHP1 expression and JNK activation. We show that proliferation of serum-or IGF-1-stimulated breast adenocarcinoma cells is negatively regulated by SHP1 and show for the first time that IGF-1-activated JNK induces SHP1 expression in MCF-7 cells used as experimental model. In an attempt to understand the mechanism by which serum-or IGF-1-activated JNK induces SHP1 expression resulting in suppression of cell proliferation, we reveal for the first time that in serum-or IGF-1-stimulated breast cancer MCF-7 cells, JNK induces SHP1 expression through the binding of AP-4 and RFX-1 transcription factors to the epithelial tissue-specific SHP1 promoter. Overall, we show for the first time that IGF-1-stimulated proliferation of breast adenocarcinoma cells is negatively regulated by SHP1 through activation of JNK. Mol Cancer Res; 9(8); 1112-25. Ó2011 AACR.

AP4 activates cell migration and EMT mediated by p53 in MDA-MB-231 breast carcinoma cells

“…As a leading type of cancer in women, breast cancer accounts for 25 % of all cases [41]. AP4 has been reported to suppress breast cancer proliferation [17,19]. Low expression of AP4 indicates good prognosis in estrogen receptor-positive breast cancer [20].…”

“…In many studies, AP4 was found to participate in cellular differentiation, cell proliferation [6][7][8][9][10], cell cycle regulation, and apoptosis [11][12][13][14][15][16]. More recent findings show that AP4 is also involved in pathological conditions, for example, AP4 is highly expressed in colon carcinoma, breast cancer, and prostate cancer [15,17,18] and that AP4 suppresses MCF-7 cell proliferation via enhancing the levels of SHP1 and JNK activation [19]. Furthermore, overexpression of AP4 is associated with poor prognosis and lymph node status of ER?…”

Human somatostatin receptor-3 distinctively induces apoptosis in MCF-7 and cell cycle arrest in MDA-MB-231 breast cancer cells

“…Constitutively phosphorylated PI3K in MDA-MB-231 as well as in R3-MB-231 cells and lack of SSTR3 cytotoxic effect in ER a -negative cells attest the importance of PI3K inhibition in apoptosis. The tyrosine phosphatase PTP-1C is highly expressed in breast tumors (Amin et al, 2011). In MCF-7 and HEK-293 cells, PTP-1C translocation from cytosol to the cell surface is an essential requirement for SSTR mediated apoptosis (War et al, 2011, Srikant andShen, 1996).…”

The Transcription Factor AP4 Promotes Oncogenic Phenotypes and Cisplatin Resistance by Regulating LAPTM4B Expression

“…proliferation by enhancing SHP1 expression and JNK activation [40]. It indicates that AP4 may play a dual role in cell proliferation via different pathways.…”