Interleukin-6 as a potential mediator of breast cancer progression and non-melanoma skin carcinogenesis

We set out to further characterize the molecular consequences of IL-6 signaling in breast cancer, focusing on those associated with poor clinical outcome. In Chapter 2, we highlight IL-6 as one of only few factors capable of inducing a carcinoma-associated epithelial-mesenchymal transition (EMT) phenotype. In particular, we demonstrated E-cadherin repression among multiple estrogen receptor-alpha (ERalpha)-positive human breast cancer cell lines following IL-6 exposure. Ectopic IL-6 expressing MCF-7 cells (MCF-7 IL-6) exhibited a gene expression profile and phenotype consistent with EMT including down-regulated E-cadherin and aberrant induction of N-cadherin, Vimentin, Twist, and Snail. Furthermore, ectopic autocrine IL-6 signaling promoted breast cancer cell invasiveness. Intriguingly, Twist, a transcriptional repressor of E-cadherin, was shown to promote IL-6 production and constitutive STAT3 phophorylation. Ectopic IL-6 expression maintained an EMT phenotype in an orthotopic xenograft model, which exhibited increased tumor cell proliferative index, advanced histologic grade, and poor tumor cell differentiation.;Chapter 3 exposes E-cadherin as a suppressor of breast cancer cell growth and IL-6 production. The objective of these studies was to characterize the mechanisms by which IL-6 promotes breast cancer cell growth. Qe hypothesized that IL-6-induced E-cadherin repression may promote breast cancer cell growth and moreover, that E-cadherin expression may inhibit breast cancer cell growth. IL-6 enhanced ERalpha-positive breast cancer cell growth in a 3-dimensional (3D) tumor growth assay (TGA) and promoted E-cadherin repression in a dose-dependent manner. Additionally, E-cadherin expression status was inversely associated with breast cancer cell growth rates. Likewise, cells which lack E-cadherin due to ectopic Twist expression showed unaffected growth following IL-6 exposure. To determine if E-cadherin inhibits breast cancer cell growth, we expressed either full-length E-cadherin or truncated E-cadherin lacking a beta-catenin binding domain (mutant E-cadherin) in MDA-MB-231 cells, a commonly used aggressive E-cadherin-negative breast cancer cell line. Full-length E-cadherin completely abrogated IL-6 production, and mutant E-cadherin induced an intermediate impairment of IL-6 production, suggesting that beta-catenin and to a lesser extent, E-cadherin adhesive activity, may mediate IL-6 expression. Full-length E-cadherin also inhibited MDA-MB-231 cell growth. Furthermore, mutant E-cadherin sustained slightly increased growth rates compared to full-length E-cadherin, suggesting that beta-catenin may regulate MDA-MB-231 growth as well as IL-6 production.;Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells with potent immunosuppressive properties and were the focus of Chapter 4. Although peripheral MDSC induction has been described in various mouse tumor models and in patients with a wide range of cancers, this is not the case for UVB-induced NMSC. IL-6, which has been shown to be up-regulated following UVB irradiation, also promotes MDSC expansion in vivo. Therefore, we conducted a pilot study to evaluate the presence of peripheral MDSC in Skh-1 tumor-bearing mice following chronic UVB exposure. We hypothesized that tumor-bearing mice would have relatively elevated MDSC levels compared to tumor-free control mice. Additionally, we hypothesized that male mice may be more susceptible to peripheral MDSC expansion due to their relatively low inflammatory response compared to females following UVB exposure.;Our preliminary results confirmed our previous report of higher UVB-induced skin tumor burden in male mice. An expanded MDSC population of splenocytes was detected in UVB-induced skin tumor-bearing mice and moreover, our findings suggest a gender discrepancy in which male mice appear more susceptible to skin tumor-induced MDSC expansion. Furthermore, relatively high compared to relatively low tumor burden mice showed more MDSC, particularly in males. (Abstract shortened by UMI.)...