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for the South China Breast Cancer Group (SCBCG) IMPORTANCE Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed.OBJECTIVE To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy.INTERVENTIONS Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m 2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. MAIN OUTCOMES AND MEASURESThe primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. RESULTS Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabinerelated adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event.CONCLUSIONS AND RELEVANCE Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival.

Recent findings have revealed that dysregulated miRNAs contribute significantly to autophagy and chemoresistance. Pharmacologically targeting autophagy-related miRNAs is a novel strategy to reverse drug resistance. Here, we report a novel function of isoliquiritigenin (ISL) as a natural inhibitor of autophagy-related miR-25 in killing drug-resistant breast cancer cells. ISL induced chemosensitization, cell cycle arrest and autophagy, but not apoptosis, in MCF-7/ADR cells. ISL also promoted the degradation of the ATP-binding cassette (ABC) protein ABCG2 primarily via the autophagy-lysosome pathway. More importantly, miRNA 3.0 array experiments identified miR-25 as the main target of ISL in triggering autophagy flux. A mechanistic study validated that miR-25 inhibition led to autophagic cell death by directly increasing ULK1 expression, an early regulator in the autophagy induction phase. miR-25 overexpression was demonstrated to block ISL-induced autophagy and chemosensitization. Subsequent in vivo experiments showed that ISL had chemosensitizing potency, as revealed by an increase in LC3-II staining, the downregulation of ABCG2, a reduction in miR-25 expression and the activation of the miR-25 target ULK1. Overall, our results not only indicate that ISL acts as a natural autophagy inducer to increase breast cancer chemosensitivity, but also reveal that miR-25 functions as a novel regulator of autophagy by targeting ULK1.

Accumulating evidence has suggested that cancer stem cells (CSCs) are at the root of drug resistance, and recent studies have indicated that caveolin-1, a membrane transporter protein, is involved in the regulation of cancer chemoresistance and stem cell signaling. However, the current understanding of the role of caveolin-1 in breast cancer development remains controversial. Herein, we demonstrate that caveolin-1 expression was upregulated after breast cancer chemotherapy in vitro and in vivo, accompanied by co-overexpression of β-catenin and ATP-binding cassette subfamily G member 2 (ABCG2) signaling. Additionally, breast CSCs were enriched for caveolin-1 expression. Caveolin-1 silencing sensitized breast CSCs by limiting their self-renewal ability but promoting the differentiation process. β-catenin silencing prevented the enhanced chemoresistance of CSCs induced by caveolin-1 overexpression, indicating that β-catenin is an essential molecule responsible for caveolin-1-mediated action. Further mechanistic investigation revealed that caveolin-1 silencing could downregulate the β-catenin/ABCG2 pathway through glycogen synthase kinase 3 beta activation and Akt inhibition, resulting in increased β-catenin phosphorylation and proteasomal degradation. Clinical investigation also revealed a close correlation between caveolin-1 and β-catenin/ABCG2 signaling in breast cancer samples. Notably, caveolin-1 was highly elevated in triple-negative breast cancer, and caveolin-1 silencing significantly impaired the tumorigenicity and chemoresistance of breast CSCs in in vivo models. Overall, our study not only highlights the role of caveolin-1 in mediating the chemoresistance of breast CSCs via β-catenin/ABCG2 regulation but also provides novel approaches for future therapies targeting CSCs.

Background: Cancer patients had been profoundly affected by the outbreak of COVID-19 especially after quarantine restrictions in China. We aimed to explore the treatment changes and delays of early breast cancer (EBC) during the first quarter of 2020. Methods: We did this retrospective, multicentre, cohort study at 97 cancer centres in China. EBC patients who received treatment regardless of preoperative therapy, surgery or postoperative therapy during first quarter of 2020 were included. Findings: 8397 patients were eligible with a median age of 50 (IQR 43À56). 0¢2% (15/8397) of EBC patients were confirmed as COVID-19 infection. Only 5¢2% of breast cancer diagnosis occurred after quarantine in Hubei compared with 15¢3% in other provinces (OR= 0¢30, 95%CI 0¢24À0¢38). postoperative endocrine