Correlation Between Biomarkers And Heterogeneity Of Invasion And Metastasis In Breast Cancer

The main obstacle in the current treatment of breast cancer is the invasion and metastasis of breast cancer cells,which maybe related to the intertumor heterogeneity in breast cancer.The development of cancer can be driven by mutations or changes in expression of a series of cancer-promoting and tumor suppressor genes.Studying the expression and the effects of these genes in the process of tumor development,invasion,and metastasis could provide reliable markers for the systematic monitoring of cancer progression,and could also provide effective targets for the treatment of breast cancer.The aims of this study were to assess the impact of breast cancer subtypes(BCS)on patterns of distant metastasis,survival,and local treatment-decision making including local surgery and axillary lymph node dissection(ALND)in patients with advanced breast cancer.In addition,we investigated the expression of replication factor C3(RFC3)in various breast cancer cells and assessed the relationship between RFC3 and the development of breast cancer.Moreover,we assessed the breast cancer-associated circular RNAs(circRNAs)by high-throughput sequencing and further analyze whether they are involved in the regulation of breast cancer progression by targeting RFC3 expression.Our findings showed that:1.There are different patterns of distant metastasis associated with different BCS.There should be a different focus in the postoperative follow-up and monitoring of breast cancer patients with different BCS.2.Distant metastases sites have differential impact on clinical outcomes in de novo stage IV breast cancer.Follow-up screening for brain and liver metastases might be effective in improving outcomes.3.Local surgery of the primary tumour was improved survival for patients with de novo stage IV breast cancer regardless of the BCS status.ALND may improve survival in patients with de novo stage IV breast cancer who received primary tumor surgery,especially in patients with hormone receptor positive/human epidermal growth factor receptor-2 overexpression and human epidermal growth factor receptor-2 overexpression.4.RFC3 was overexpressed in human primary breast cancer samples compared with matched adjacent non-tumor tissues.In vitro study,RFC3 was highly expressed in breast cancer cell lines,especially in the triple negative breast cancer(TNBC)cell lines MDA-MB-231 and MDA-MB-468,compared to the non-tumor immortalized human breast epithelial cell line MCF-10A.RFC3 overexpression was an independent adverse prognostic factor of patient outcomes.Up-regulation of RFC3 promotes TNBC progression through epithelial-mesenchymal transition signal pathway.Therefore,RFC3 could be an independent prognostic factor and therapeutic target for TNBC.5.High-throughput RNA sequencing was performed to obtain an unbiased profile of circRNA expression.We found a total of 152 circRNAs were differentially expressed in breast cancer tissues,among which 85 were up-regulated and 67 down-regulated.Out of these,hsa_circ₀011946 was selected and the subsequent bioinformatics analysis predicted that hsa_circ₀011946 sponging miR-26a/b directly targeted RFC3 and that its knockdown could inhibit RFC3 mRNA and protein expression.Furthermore,knockdown of hsa circ 0011946 significantly suppressed the migration and invasion of Michigan Cancer Foundation-7 cells.Our findings showed that hsa circ 0011946 and RFC3 comprise a novel pathway involved in the progression of breast cancer.This study provides a new theoretical basis for the individualized development of treatment strategies and therapeutic targets for breast cancer by systematically studying biomarkers related to the heterogeneity of invasion and metastasis in breast cancer.