The Clinical And Translational Study Of HER2 Overexpressed Breast Cancer

Background:Breast cancer is a kind of malignancy that originates from the breast and is the most common malignancy in women.Human epidermal growth factor receptor 2 is overexpressed in 20%～25%of invasive breast cancers,and its overexpression is related to the invasiveness and survival rate of breast cancer.There is evidence that long non-coding RNA(lncRNA)HOTTIP is highly expressed in various cancers and can promote the growth and invasiveness of cancer cells.However,the mechanisms of the roles lncRNA HOTTIP plays in the occurrence and development of HER2-positive breast cancer remains unclear.Therefore,this study aimed to explore the effect of IncRNA HOTTIP knockdown on trastuzumab in HER2-positive breast cancer.Methods:In this study,we firstly used human HER2-overexpressed breast cancer cell lines BT474 and SK-BR-3 to construct BT474/TR and SK-BR-3/TR cell lines.We processed the cell line with trastuzumab to obtain a stable drug-resistant cell line SK-BR-3-TR.The MTT method was used to identify SK-BR-3-TR cells.We then used lentiviral transfection and other methods to obtain the si-HOTTIP-SK-BR-3-TR cell line needed for the experiment for subsequent animal models.In addition,we used Cell Counting Kit-8 to detect the effect of cell viability and IncRNA HOTTIP knockdown on cell growth.RT-qPCR was used to detect the level of IncRNA HOTTIP.The number of apoptotic cells was detected by annexin V/propidium iodide staining.Western blotting was used to detect the expression levels of β-catenin,c-Myc and cleaved caspase-3.The Transwell experiment was used to study the invasion of trastuzumab-resistant breast cancer cells.Results:The IncRNA HOTTIP significantly promoted the resistance of breast cancer cells to trastuzumab.Knockdown of the lncRNA HOTTIP significantly inhibited the viability,proliferation,and invasion of trastuzumab-resistant breast cancer cells.Meanwhile,the knockdown of HOTTIP notably induced the apoptosis of trastuzumab-resistant breast cancer cells via downregulation of β-catenin/c-Myc axis.In addition,overexpression of HOTTIP enhanced trastuzumab resistance.Overall,by inhibiting the Wnt/β-catenin pathway,knocking down the long non-coding RNA HOTTIP enhanced the sensitivity of breast cancer to trastuzumab.Conclusions:In this study,we found that knocking down the lncRNA HOTTIP can inhibit cell viability,inhibit proliferation,induce apoptosis,and inhibit the invasion of trastuzumab-resistant breast cancer cells by modulating the Wnt/β-catenin signaling pathway.These data indicate that lncRNA HOTTIP can be used as a new target for the treatment of HER2-overexpressed breast cancer.Background:Breast cancer is currently the world’s most common malignant tumor and one of the most important factors threatening women’s health.In the clinical diagnosis and treatment of breast cancer,the overall survival rate is usually used to assist breast cancer treatment and prognosis analysis.Considering that the risk of death will change over time,the conditional survival rate(CS)can be used to describe the survival situation more accurately.This study aims to evaluate the accuracy of conditional disease-specific survival(CDS)in women with operable invasive breast cancer and analyze its implications for clinical treatment.Methods:The data for this study comes from the surveillance,epidemiology and end result program of the National Cancer Institute(SEER).Use R language and non-parametric test in the kernel density smoothing method to calculate the hazard rate.The Kaplan-Meier method and log-rank test were used to estimate and compare the disease-specific survival rate(DSS).Use Cox regression model to adjust for confounding factors.Conditional disease-specific survival rate is calculated by CDS(y|x)=DSS(x+y)/DSS(x),where DSS(x)represents the disease-specific survival rate for x years.Results:The 5-year,10-year and 15-year disease-specific survival rates were 88.7%,82.0%and 78.3%,respectively.The hazard rate after surgery began to rise,peaked in about 1.5 years,and then gradually decreased.At the same time,the conditional disease-specific survival rate drops after surgery,and then continues to rise,showing the opposite trend to the hazard rate.There is a larger survival gap between the cumulative disease-specific survival rate of patients with high-risk factors and the conditional disease-specific survival rate.The changing trend of the conditional disease-specific survival rate of patients with high-risk factors is more obvious,and the gap of conditional disease-specific survival rate between low-risk patients and high-risk patients has gradually narrowed over time.Conclusion:Compared with traditional cumulative survival,conditional survival rate can provide a more accurate long-term prognostic assessment,especially for high-risk long-term survivors.