Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-ocpositive breast cancer

Introduction: Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-alpha (ER alpha)positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. Methods: The role of the phosphorylated signal transducer and activator of transcription. 3 pathway was investigated in.ER alpha-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ER alpha-positive breast cancer cell lines alone or following treatment with 10 rig in L recombinant IL-6 or human marrow stromal cell-conditioned media., with or without siltuximab (a. neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenviroimient-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ER alpha-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ER alpha-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo. Results: In eight of nine. ER alpha-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of ST AD. Differential gene expression analysis identified 17 genes that could he used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ER alpha-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (>= 10 pg/mL). When human IL-6 was provided in vivo, MCT-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated. mice at MCF-7 engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone 'induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of SC expressing human 11,6 and estrogen. Conclusion: Given the established role for IL-6 in ER alpha-positive breast cancer, these data demonstrate the potential for anti-IL-6 thER alpha peutics in breast cancer.