Abstract LB-101: Crosstalk between stromal components and endocrine resistant breast cancer via secreted factors enhances tumor growth and metastasis

Abstract

Abstract Various endocrine therapies have been developed such as selective estrogen receptor modulation (SERM), selective estrogen receptor downregulator (SERD) and ligand deprivation using aromatase inhibitors (AI). Tamoxifen (TAM), a SERM and AIs are the most commonly used adjuvant treatment for postmenopausal women with early-stage estrogen receptor positive breast cancer. Despite the relative safety and significant anti-neoplastic and chemopreventive activities of tamoxifen and AIs, many initially responsive breast tumors develop resistance and ultimately recur. Many underlying molecular events that confer resistance are known, but a unifying theme is yet to be revealed. While the tumor microenvironment is being increasingly recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escaping, and distant metastasis, our previous work shows that the critical molecular and cellular players secreted from a crosstalk between breast cancer cells, and stromal cells can regulate the tumor growth and process of metastasis in breast cancer. In this report, we established a tamoxifen-resistant breast cancer (TAMR) cells. We screened secretomes from normal fibroblasts in co-culture of TAMR cells using cytokine antibody arrays to target 105 human cytokines simultaneously. We identified upregulation of IL-6, CXCL5, IL-8, EMMPRIN, CXCL1, GM-CSF, GDF-15, CCL5, BDNF, BAFF, LIF, and CXCL10 in the secretomes from fibroblasts in crosstalk of ERBC cells. We ranked the expression level of each factor by real-time qRT-PCR and determined that CXCL1 and IL-6 were the top candidates. We confirmed by U-PLEX (MSD) that CXCL1 and IL-6 secreted from fibroblasts treated with TAMR tumor-conditioned medium (TCM) was upregulated compared to treatment with serum free media (SFM). Our data showed that the proliferation of TAMR cells co-cultured with fibroblasts was enhanced compared to monoculture. Furthermore, TAMR cell migration, a key step in tumor metastasis, was promoted by conditioned medium (CM) from TCM-induced fibroblasts. Significantly, inhibition of the CXCL1 and IL-6 signaling pathway by Reparixin, an inhibitor of the CXCL1 receptor CXCR1/2, and Tocilizumab, an inhibitor of the IL-6 receptor abrogated TAMR cell growth and migration. These findings implicate IL-6 and CXCL1 signaling as a critical event in ERBC tumor growth and metastasis via crosstalk between cancer cells and stromal components. Further, these studies suggest that IL-6 and CXCL1 act as key regulators orchestrating ERBC. Therefore, we have provided evidence that supports the hypothesis that functional inhibition of the IL-6 and CXCL1 signaling pathway has the potential to circumvent ERBC growth and metastasis. Citation Format: Kideok Jin. Crosstalk between stromal components and endocrine resistant breast cancer via secreted factors enhances tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-101.