Abstract 4862: Autocrine secreted IL-6 and IL-8 play critical and non-redundant roles in basal-like breast cancer cell transformation and growth in vitro and in vivo

Abstract

Abstract Breast cancer is a heterogeneous disease that can be subdivided into distinct types based upon the molecular classification of oncogenic driver mutations. While most breast cancers are driven by estrogen-mediated signaling (ER+) or HER2 expression (HER2+), the cellular signals that mediate transformation and growth of ER-HER2- (or basal-type) breast cancers are incompletely understood. To identify novel targets for the treatment of this aggressive and treatment-refractory disease, we investigated inflammatory signaling in these cancers, as inflammatory pathways have proven critical for oncogenic transformation of multiple cancers. In our primary analysis, we analyzed ER- and ER+ primary patient tumors (N=106, Baylor College of Medicine Tumor Bank) to determine inflammatory genes (in the KEGG Cytokine-Cytokine Receptor set, N=226) that are differentially expressed (FDR<.05) in ER-negative breast cancers. Combining this analysis with analyses of the Richardson (GSE5460, N=129), Bild (GSE3143, N=158), Wang (GSE2034, N=287), Børrensen-Dale (GSE19783, N=115), and Chin Datasets (E-TABM-158, N=119), we identified a consensus set of 58 differentially regulated inflammatory genes in ER- breast cancers. To determine which genes are required for the autocrine maintenance of transformation, we performed further microarray analysis of breast cancer cell line datasets, which revealed 24 of these genes to be highly expressed in basal-like breast cancer cells in vitro. Using a lentiviral shRNA panel targeting these conserved genes, we systematically investigated their role in regulating cell growth and transformation of basal-like breast cancer. We found that suppression of 8 different inflammatory genes inhibited anchorage-independent growth in the majority of basal-like breast cancer cells, including IL-6 and IL-8. As these genes were coordinately expressed at high levels by tumor cells and associated with poor survival, they became the focus of our subsequent investigations. These studies revealed that while IL-6 expression regulated cell growth in vitro, IL-8 had stronger effects on cell migration and invasion in vitro. Notably, tandem inhibition of IL-6 and IL-8 drastically inhibited anchorage-independent growth, elicited low level apoptosis, and sensitized cells to chemotherapeutic agents. In vivo, IL-6 inhibition limited tumor growth but had no effect on tumor formation, while IL-8 inhibition prevented tumor formation in some animals. Strikingly, dual inhibition of IL-6 and IL-8 strongly inhibited tumor engraftment and growth in vivo. These findings suggest that specific inflammatory pathways regulate the growth and maintenance of basal-like breast cancer transformation and suggest that combined inhibition of IL-6 and IL-8 inflammatory pathways represents a promising strategy to treat or prevent basal-like breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4862. doi:1538-7445.AM2012-4862