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The S100A7-c-Jun Activation Domain Binding Protein 1 Pathway Enhances Prosurvival Pathways in Breast Cancer

Departments of ¹ Biochemistry and Medical Genetics and ² Pathology, University of Manitoba; ³ Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada; ⁴ Basic Medical Sciences, Memorial University of Newfoundland and College of the North Atlantic, Clarenville Campus, Clarenville, Newfoundland, Canada; and ⁵ Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Peter H. Watson, Department of Pathology, University of Manitoba, D212-770 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0W3. Phone: 204-789-3435; Fax: 204-789-3931; E-mail: pwatson{at}cc.umanitoba.ca.

S100A7 is among the most highly expressed genes in preinvasive breast cancer, is a marker of poor survival when expressed in invasive disease, and promotes breast tumor progression in experimental models. To explore the mechanism of action, we examined the role of S100A7 in cell survival and found that overexpression of S100A7 in MDA-MB-231 cell lines promotes survival under conditions of anchorage-independent growth. This effect is paralleled by increased activity of nuclear factor-B (3-fold) and phospho-Akt (4-fold), which are known to mediate prosurvival pathways. S100A7 and phospho-Akt are also correlated in breast tumors examined by immunohistochemistry (n = 142; P < 0.0001; r = 0.34). To explore the underlying mechanism, we examined the role of a putative c-Jun activation domain-binding protein 1 (Jab1)–binding domain within S100A7 using a panel of MDA-MB-231 breast cell lines stably transfected with either S100A7 or S100A7 mutated at the Jab1 domain. Structural analysis by three-dimensional protein modeling, immunoprecipitation, and yeast two-hybrid assay and functional analysis using transfected reporter gene and Western blot assays revealed that the in vitro effects of S100A7 on phospho-Akt and the nuclear factor-B pathway are dependent on the Jab1-binding site and the interaction with Jab1. Enhanced epidermal growth factor receptor signaling was also found to correlate with the increased phospho-Akt. Furthermore, the Jab1-binding domain is also necessary for the enhanced tumorigenicity conferred by S100A7 expression in murine xenograft tumors in vivo. We conclude that the S100A7-Jab1 pathway acts to enhance survival under conditions of cellular stress, such as anoikis, which may promote progression of breast cancer.

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