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Triple‐negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor‐2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC‐2036 inhibited the proliferation, invasion, migration and epithelial‐mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC‐2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC‐2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC‐2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt‐NFκB signaling to exert its antitumor effect in TNBC. DCC‐2036 also inhibited the growth and metastasis of xenografted MDA‐MB‐231 cells (AXL/MET‐high TNBC cells) but not MDA‐MB‐468 cells (AXL‐low TNBC cells) in NSG mice in vivo. Furthermore, DCC‐2036 significantly inhibited tumor growth and invasion of AXL/MET‐high TNBC PDX tumors but not AXL/MET‐low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC‐2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC‐2036 even at a high dosage. Therefore, DCC‐2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.

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Purpose Pokemon, also known as ZBTB7A, belongs to the POZ and Krüppel (POK) family of transcription repressors and is implicated in tumor progression as a key proto-oncogene. This present study aimed at determining the mechanism by which Pokemon inhibits transforming growth factor β (TGFβ)-Smad4 pathway-dependent proliferation arrest of breast cancer cells via specificity protein 1 (SP1). Methods Over-expressing plasmid or small interfering RNA (siRNA) transfection was used to regulate Pokemon levels. The EdU incorporation assay, MTS assay, and clone formation were used to identify the inhibitory effect of Pokemon siRNA on cell proliferation. Quantitative real-time polymerase chain reaction assay confirmed that Pokemon deletion inhibited the expression of proliferation-associated genes. The dual-luciferase reporter assay, electrophoretic mobility shift assay, and co-immunoprecipitation assay were used to analyze binding between Pokemon, Smad4, and SP1. Results Pokemon deletion induced proliferation arrest of breast cancer cells and inhibited the expression of proliferation-associated genes, especially Smad4 . Pokemon bound with SP1 to interdict Smad4 promoter activity. Information on clinical samples was obtained from The Cancer Genome Atlas data, in which the Pokemon mRNA levels showed a negative correlation with Smad4 levels in different subtypes of breast cancer in two independent datasets. Conclusion We demonstrated that Pokemon binds to SP1 to down-regulate Smad4 expression, thereby promoting proliferation of breast cancer cells. This suggests that Pokemon is a potential TGFβ-signaling participant in breast cancer progression.

Lynch syndrome is the most prevalent form of familial colorectal cancer (CRC) and is caused by pathogenic germline mismatch repair (MMR) gene mutations. MLH1, MSH2 and MSH6 mutations have been well studied, but the rate and characteristics of PMS2 mutations are rare, especially in China. This study enrolled 1706 unselected patients with CRC who underwent colorectal resection from June 2016 to November 2018, the MMR status and clinicopathological features were analysed. A total of 11.8% of patients with CRC had defects in at least one MMR-related protein. Among them, 8.3% were identified with PMS2 defects, and 3.1% of patients had isolated PMS2 defects. Compared with MMR-proficient CRC, PMS2-defect CRC occurred more frequently in the right colon and less frequently in the rectum, had more poorly differentiated and mucinous carcinoma cases, and had fewer perineural invasions and a lower pN stage but a more advanced pT stage and a larger tumour size. In the cases with PMS2 defect, there were fewer tumours in the right colon, fewer poorly differentiated cases and smaller tumour sizes than in the cases with both MLH1 and PMS2 defects. In addition, in cases with isolated PMS2 defects, there were more tumours in the right colon and, more mucinous carcinoma cases than in cases with MMR-proficient CRCs, but had a similar cancer onset age. This study identified the rate, clinicopathological and age characteristics of PMS2 defects in CRCs in China and highlighted the importance of universal screening and germline detection of PMS2 in CRC.