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

Abstract

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 anchorageindependent growth. This effect is paralleled by increased activity of nuclear factor-KB (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-KB 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. (Cancer Res 2005; 65(13): 5696-702)

Reciprocal negative regulation between S100A7/psoriasin and β-catenin signaling plays an important role in tumor progression of squamous cell carcinoma of oral cavity

“…Therefore, the reciprocal negative regulation between S100A7 and b-catenin signaling highlights their important roles in tumor development and tumor progression. In contrast to our findings are previous studies of breast cancer MDA-MB-231 and MDA-MB-468 cells that suggested that S100A7 expression promotes tumor growth in nude mice (Emberley et al, 2003a(Emberley et al, , 2005Krop et al, 2005). This discrepancy may be attributed to the biological differences between squamous and secretory epithelial cells, which are derived from distinct stem cell lineages.…”

S100A7 (psoriasin) is induced by the proinflammatory cytokines oncostatin-M and interleukin-6 in human breast cancer

“…Although our data are preliminary this is intriguing, given previous observations that S100A7 itself may promote EGF expression and is involved in EGFR signaling (Emberley et al, 2005;Paruchuri et al, 2008;Wang et al, 2008). We have confirmed by analysis of expression levels in an independent breast tumor data set (UNC) that S100A7 correlates with EGFR expression in a large unselected cohort and within the ER-negative subset, supporting the existence of functional cooperativity between S100A7 and EGFR (Supplementary Table S2).…”

“…Each of these cytokines has the capacity to signal, either directly or indirectly, through STAT3, ERK1/2 and PI3K (Heinrich et al, 2003;Pestka et al, 2004;Gaffen, 2008;Perrier et al, 2008). We have shown previously that S100A7 in breast tumors correlates with Akt activation (Emberley et al, 2005) and now show that OSM and IL-6 can induce S100A7 via PI3K, ERK1/2 or STAT3. We speculate that this may reflect convergence of all three pathways on the same regulator of S100A7.…”

“…Thus, activation of PI3K, ERK1/2 and STAT3 all appear to be necessary for full S100A7 induction by OSM or IL-6. We (Emberley et al, 2005;Wang et al, 2008) and others (Paruchuri et al, 2008) have previously shown a link between S100A7 and the epidermal growth factor (EGF) pathway. IL-6 and EGF signaling can also be functionally linked (Badache and Hynes, 2001).…”

“…S100A7 is over-expressed in ductal breast carcinomas, in which it associates with aggressive, high grade, estrogen receptor alpha (ER)-negative tumors, prominent leukocyte infiltration and poor patient outcome (Al-Haddad et al, 1999;Emberley et al, 2003a, b;2004a, b), consistent with its stimulatory effects on pro-survival and invasive pathways in breast cells, including PI3K, nuclear factor-kB (NFkB) and AP-1 (Emberley et al, 2005). Although S100A7 can have both pro-and anti-tumorigenic effects in vitro, it consistently promotes tumorigenesis in vivo based on two breast xenograft mouse models, in which its expression is either upregulated in MDA-MB-231 cells or reduced in MDA-MB-468 cells (Emberley et al, 2003a, b;Krop et al, 2005;Paruchuri et al, 2008).…”