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-Positive Breast Tumor Cells through Multiple Molecular Cross-talks
Cancer Research Unit, VA Medical Center, Kansas City, Missouri and Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas
Requests for reprints: Sushanta K. Banerjee, Cancer Research Unit, Research Division 151, VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128. Phone: 816-861-4700, ext. 57057; Fax: 816-922-3320. E-mail: sbanerjee2{at}kumc.edu
Epidermal growth factor (EGF) is a mitogen for estrogen receptor (ER)–positive breast tumor cells, and it has been proven that EGF occasionally mimicked estrogen action and cross-talks with ER-
to exert its activity. Therefore, the present study was undertaken to explore whether EGF is able to modulate the expression of Wnt-1-induced signaling protein-2/connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed 5 (WISP-2/CCN5), an estrogen-responsive gene, in normal and transformed cell lines of the human breast and, if so, whether this induction is critical for EGF mitogenesis and what downstream signaling pathways are associated with this event. Here, we show that EGF-induced WISP-2 expression in ER- and EGF receptor–positive noninvasive MCF-7 breast tumor cells was dose and time dependent and that expression was modulated at transcription level. A synergism was seen in combination with estrogen. Moreover, small interfering RNA–mediated inhibition of WISP-2/CCN5 activity in MCF-7 cells resulted in abrogation of proliferation by EGF. The multiple molecular cross-talks, including the interactions between phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase signaling pathways and two diverse receptors (i.e., ER- and EGFR), were essential in the event of EGF-induced WISP-2/CCN5 up-regulation in MCF-7 cells. Moreover, EGF action on WISP-2/CCN5 is restricted to ER- and EGFR-positive noninvasive breast tumor cells, and this effect of EGF cannot be instigated in ER--negative and EGFR-positive normal or invasive breast tumor cells by introducing ER-. Finally, regulation of phosphorylation of ER- and EGFR may play critical roles in EGF-induced transcriptional activation of WISP-2 gene in breast tumor cells.
Key Words: ER- • EGF • gene expression • phosphorylation • signal transduction and WISP-2/CCN5 signaling
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