Abstract LB-101: Crosstalk between stromal components and endocrine resistant breast cancer via secreted factors enhances tumor growth and metastasis
Authors: Jin Kideok 
Published: August 2018

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.