Abstract P6-03-02: Chronic CXCL12 exposure induces a metastatic phenotype in ER-positive breast cancer cells through transcriptional reprogramming

Abstract

Abstract The chemokine CXCL12 is transcriptionally activated by estrogen in estrogen receptor (ER)-positive breast cancer cells. We have found that CXCL12 signaling is essential to maintain the long-term growth of ER-positive breast cancer cells and promotes cancer cell growth in the absence of estrogen. Chronic blockade of CXCL12 signaling with AMD3100, an inhibitor of CXCL12 receptor CXCR4, causes cell death in these cells. Chronic exposure to CXCL12 reprograms ER-positive breast cancer cells through genome-wide transcriptional changes and activates numerous signaling pathways including EMT and the inflammatory response. Many ER target genes are activated in CXCL12-reprogrammed cells even in the absence of estrogen which leads to the diminished estrogen modulated transcription in these cells. These cells also show enhanced signaling via TGFb, EGFR and Rac1 pathways, rendering these cells more sensitive to the CDK7 inhibitor, THZ1, and to drug combinations of THZ1 with the EGFR inhibitor Gefitinib or the RAC1 inhibitor EHT 1864. Furthermore, CXCL12-reprogrammed ER-positive breast cancer cells become more motile in vitro and display a metastatic phenotype in a mouse model. The lung-tropic phenotype of CXCL12-reprogramed MCF-7 cells could be explained by increased expression of integrins and pro-inflammatory signaling molecules. Our novel finding of chronic CXCL12 action on ER-positive breast cancer cells suggests a mechanism by which the interaction between stromal and tumor cells leads to increased breast tumor metastatic potential. Citation Format: Sun J, Slingerland JM, Lippman ME. Chronic CXCL12 exposure induces a metastatic phenotype in ER-positive breast cancer cells through transcriptional reprogramming [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-03-02.