A. -. Maiti1, M. Okano1, I. Okano1, T. Kawaguchi1, K. Takabe1, N. Hait1, A. Maiti1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA
Introduction: ~~Breast cancer most often recurs and metastasizes to the distal organs that had their primary tumors surgically excised. Functional analysis of organ-specific metastasis genes suggested that there might be two different categories of metastasis genes. One group of genes has the role in tumor growth and survival besides their metastasis function while another group of genes only have a specific role in facilitating adaptation of tumor cells at distant sites and do not have a clear role in promoting primary tumor growth.In this study, we assessed the specific cancer-related gene expression changes occurring with metastatic breast cancer recurrence to distant organs comparing with non-metastatic breast cancer.
Methods: ~~RNA-sequencing was done using two cell lines 4T1-luc2 that can only metastasize to lung and 4T1.2-luc2 metastasized to bone and lung suggested that at least 50 genes which are statistically highly expressed in 4T1.2-luc2 compared to 4T1-luc2 cells. Out of which only a few genes well established for cancer metastasis biology include ANGPTL77, SERPINE2, TSPAN11, ESM1, LCN2 which expressed over 8 fold in 4T1.2-luc2 compared to 4T1-luc2 cells. A metastatic syngeneic mouse model was developed and metastatic growth to distant organs was monitored using IVIS and MRI imaging after the primary tumor was surgically excised from mice.
Results:~~Our animal model tumor molecular analysis data revealed that LCN2 (7 fold) and CD133 (above 20 fold) over-expressed in the spine and bone compared to the primary or lung met lesions formed by 4T1.2-luc2. Conversely, LCN2 and CD133 genes are downregulated in breast cancer lung metastasis tissues, while CD151, EPHA2, and TWIST1 genes highly overexpressed in lung metastatic lesion compared to primary, bone or spine. Further, the RNA-seq data of patient samples explained that LCN2, CD133 expressions are significantly higher (8 out of 10 patients) in advanced breast cancer bone metastases compared with matching non-metastatic breast cancer.
Conclusion:~~Our data suggested that LCN2, CD133 would be a prognostic marker for breast cancer spinal bone metastasis, while CD151, TWIST1, EPHA2 would be a prognostic marker for lung metastasis and organ-specific relapse.