Project description:Triple-negative breast cancer (TNBC) has a relatively aggressive biological behavior and poor outcome. Our published study showed that PAI-1 could induce the migration and metastasis of TNBC cells. However, the underlying mechanism by which PAI-1 regulates TNBC metastasis has not been addressed. Using microarray analysis of lncRNA expression profiles, we identified a lncRNA SOX2-OT, which is by induced by PAI-1 and could function as an oncogenic lncRNA in TNBC.
Project description:Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and marked sensitivity to TM. Global proteomic and metabolomic profiling identified TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We identified the AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricted copper deficiency to mitochondria and phenocopied TM-mediated alterations. These findings identify a novel copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials.
Project description:This study explored the expression, biological function and prognostic role of SOX2 in triple negative breast cancer (TNBC). Quantitative real-time PCR and immunohistochemistry were used to detect the expression of SOX2 in TNBC cell lines and clinical tissues. MTT assay, Transwell assay, flow cytometry and xenograft mouse model were used to assess the biological functions of SOX2. It was found that SOX2 was up-regulated in both TNBC cell lines and clinical tissues. High expression of SOX2 was associated with shorter overall survival and disease free survival. Moreover, inhibition of SOX2 suppressed cell proliferation and invasion, induced cell apoptosis in vitro, and suppressed tumorigenesis and metastasis in vivo. In addition, analysis of TNM stage and lymph nodes infiltration among the 237 TNBC patients by paired χ2 test showed that SOX2 was inversely correlated with tumor status, our findings provided evidence that SOX2 acts as a tumor promoter in TNBC and inhibition of SOX2 could be a potential therapeutic strategy for TNBC.
Project description:Purpose: To understand the underlying mechanisms of oncolytic virus therapy in breast cancer. Methods: The primary tumors of 4T1 in BALB/C mice were exstracted and analyzed by RNA-seq. Results: In consistent with previous studies, we found some anti-tumor factors were up-regulated. Interestingly, several immunosupressive genes were activited. Conclusion: Our study identified the intercellular and intracellular factors restricting the optimized oHSV efficacy and supported the rationally designed triple therapy for clinical translation.
Project description:Purpose: To understand the underlying mechanisms of oncolytic virus therapy in breast cancer. Methods: The primary tumors of 4T1 in BALB/C mice were extracted and analyzed by RNA-seq. Results: In consistent with previous studies, we found some anti-tumor factors were up-regulated. Interestingly, several immunosupressive genes were activited. Conclusion: Our study identified the intercellular and intercellular factors restricting the optimized oHSV efficacy and supported the rationally designed triple therapy for clinical translation.
Project description:Sox2 has been studied in several types of human solid tumors. The investigators found that Sox2 had higher expression level in colorectal cancer and metastatic tissues than normal tissues. So the investigators assumed that whether Sox2 plays an important role in the progression and migration of colon cancer.