Abstract 1479: Targeting breast cancer bone metastases looking at the cross-talk between tumor cells and bone environment
Authors: Bottos Alessia , Gill Jason , Wodnar-Filipowicz Aleksandra , Hynes Nancy E. 
Published: August 2012

Metastatic dissemination is a major cause of cancer associated death; in breast cancer, bone, lung and brain are the major sites of tumor relapse. Bone marrow (BM) is a reservoir for metastatic breast cancer cells that can enter into a quiescent state and remain latent even for decades after dissemination. By still unknown mechanisms, dormant tumor cells can reacquire proliferative ability, thereby causing osteolytic or osteoblastic lesions. During these processes BM environment and tumor cells strongly influence each other. We aimed to analyze molecular mechanisms involved in the liaison between tumor cells and BM microenvironment. More specifically, we investigated how breast cancer cells can affect BM stoma when they home to the endosteal niche and how bone microenvironment can influence the behavior of tumor cells. We took advantage of the MDA-MB231 SCP1833 subclone, which after intracardiac injection has a high propensity for bone metastases. Tumor cell dissemination was followed by bioluminescence imaging and when BM metastases were detected different cell populations from the bone environment were isolated by cell sorting. We excluded cells of the hematopoietic compartment from the analysis, concentrating on the CD45- population. We used the best available antibodies that define osteoblast (CD45-, TR119-, Sca1-, CD51+), endothelial cells (CD45-, TR119-, Sca1+, CD31+) and mesenchymal progenitors (CD45-, TR119-, CD31-, Sca1+) for sorting in order to compare BM populations from tumor-bearing mice with un-injected control mice by a genome wide-transcriptome study. Microarray analysis revealed that BM is strongly affected by breast cancer cell dissemination. Indeed, several components of key molecular pathways involved in tumor development (including TGFBR, PDGFRB, EGFR, HGFR and IGFR signaling pathways) are modulated in the BM of mice with tumor cells. We are following up this analysis by testing the effects of the PI3K-mTOR inhibitor BEZ-235 in breast cancer bone metastases. PIK3CA, that is a downstream effector of several of the above-mentioned pathways, is up-regulated in the bone stroma of tumor-bearing mice. Besides the effect of BEZ-235 on tumor cells, we want to elucidate how the BM responds to PI3K pathway inhibition, and how this influences survival and proliferation of tumor cells. To investigate the effect of BM environment on disseminated tumor cells, we compared the expression profile of MDA-MB231 SCP1833 from the mammary fad pad, i.e, the primary tumor, with tumor cells isolated from BM. We have uncovered some transcripts for surface proteins whose expression is down-regulated in cancer cells that have homed to the BM, compared to tumor cells growing in the mammary fad pad. These and other results that will be presented show the important role that the environment plays on the tumor cell transcriptome and ultimately on the response to therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1479. doi:1538-7445.AM2012-1479