Abstract 3530: The role of IL-6 in ERα+ breast cancer and potential use for Siltuximab, an anti-IL-6 antibody, in ERα+ breast cancer treatment.
Authors: Axel Amy , Casneuf Tineke , King Peter , Alvarez JD , Hall Brett , Sasser Kate 
Published: August 2014

Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-alpha (ERα) positive breast cancer. High IL-6 serum levels are associated with poor prognosis in ERα+ breast cancer patients, and IL-6 related polymorphisms that lead to elevated IL-6 expression are associated with decreased overall survival (PMID 17261184, 12771987). Preclinical data suggest that in contrast to ERα negative breast cancer cell lines, ERα positive cell lines rarely produce autocrine IL-6, and are therefore dependent on paracrine IL6 produced by the microenvironment. Furthermore, when ERα positive cell lines are exposed to paracrine IL-6, phosphorylation of STAT3-Y705, increased growth rates and more aggressive tumor phenotypes are observed (PMID 17586727, 18974155, 19581928). We utilized 3D co-cultures and heterotypic xenograft models to investigate the ability of siltuximab, an anti-IL-6 antibody in clinical development, to attenuate paracrine IL-6 effects across a panel of 8 ERα positive breast cancer cell lines and heterotypic xenograft models. From a panel of 8 ERα postive breast cancer lines, 75% responded to recombinant human IL-6 (hIL-6) protein by phosphorylation of STAT3 (Ty705), but not AKT, MEK1/2, or ERK1/2. Siltuximab treatment blunted pSTAT3 induction in all IL-6 responsive ERα positive breast cancer lines but failed to reduce pSTAT3 phosphorylation in three ERα negative cell lines that produced autocrine IL-6. The 3D tumor growth assay demonstrated accelerated growth rates for ERα positive breast cancer lines in the presence of IL-6 or human mesenchymal stem cells (hMSC), which returned to baseline with siltuximab treatment. In addition, when hIL-6 was supplemented in vivo, the ERα positive tumor cell line, MCF-7 engrafted without the need for estrogen supplementation and tumor growthblunted with siltuximab treatment. When tumors were allowed to establish before treatment, siltuximab was able to induce tumor regressions in all treated animals (10/10). Tumor regression was associated with decreased mitotic counts in tumors. In addition to these experiments, we investigated STAT3 activation in a panel of primary patient-derived ERα positive breast cancer samples. 43% of samples demonstrated activated STAT3 as determined by Y705 phosphorylation. These same ERα positive breast cancer patients displayed an activated IL-6 network as assessed by an a priori 32-gene IL-6 network gene expression profile signature and was also associated with increased IL-6 serum levels. This activated IL-6 gene signature was also associated with ERα positive tumors and increased metastasis as assessed by positive node status in four independent breast cancer data sets. Taken together, these data suggest a key role for IL-6 in estrogen independent ERα positive breast cancer progression.

Citation Format: Amy Axel, Tineke Casneuf, Peter King, JD Alvarez, Brett Hall, Kate Sasser. The role of IL-6 in ERα+ breast cancer and potential use for Siltuximab, an anti-IL-6 antibody, in ERα+ breast cancer treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3530. doi:10.1158/1538-7445.AM2013-3530