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Ubiquitination and deubiquitination have emerged as critical regulators in cancer. In the present study, the expression pattern of 50 ubiquitin-specific proteases (USPs) was summarized in breast cancer using a bioinformatics approach, and USP21 was identified as the most altered gene in breast cancer. In particular, expression of USP21 in triple negative breast cancer (TNBC) cell lines was greater compared with other subtypes of breast cancer. Knockdown of USP21 in TNBC cells inhibited cell proliferation, migration and invasion. Microarray profiling of the USP21 knockdown cells revealed significant downregulation of multiple genes associated with the NOD-like receptor signaling pathway. The results of the present study suggest that USP21 has a significant role in TNBC progression, and therefore may represent a novel therapeutic target.

Submit your article to this journal Keywords: calreticulin exposure, CrossMab, HER2-overexpressing breast cancer, pertuzumab, trastuzumab, T cell immunity Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; CDR, complementarity determining region; CH1, constant heavy chain 1; CL, constant light chain; CRT, calreticulin; FCM, flow cytometry; HER, human epidermal growth factor receptor; HER2-ECD, extracellular domain of HER2; LDH, lactate dehydrogenase; mAb, monoclonal antibody; PBMCs, peripheral blood mononuclear cells; PI3K, phosphatidylinositol 3-kinase; SEC, size-exclusion chromatography.Although trastuzumab has succeeded in breast cancer treatment, acquired resistance is one of the prime obstacles for breast cancer therapies. There is an urgent need to develop novel HER2 antibodies against trastuzumab resistance. Here, we first rational designed avidity-imporved trastuzumab and pertuzumab variants, and explored the correlation between the binding avidity improvement and their antitumor activities. After characterization of a pertuzumab variant L56TY with potent antitumor activities, a bispecific immunoglobulin G-like CrossMab (Tras-Permut CrossMab) was generated from trastuzumab and binding avidity-improved pertuzumab variant L56TY. Although, the antitumor efficacy of trastuzumab was not enhanced by improving its binding avidity, binding avidity improvement could significantly increase the anti-proliferative and antibody-dependent cellular cytotoxicity (ADCC) activities of pertuzumab. Further studies showed that Tras-Permut CrossMab exhibited exceptional high efficiency to inhibit the progression of trastuzumab-resistant breast cancer. Notably, we found that calreticulin (CRT) exposure induced by Tras-Permut CrossMab was essential for induction of tumor-specific T cell immunity against tumor recurrence. These data indicated that simultaneous blockade of HER2 protein by Tras-Permut CrossMab could trigger CRT exposure and subsequently induce potent tumor-specific T cell immunity, suggesting it could be a promising therapeutic strategy against trastuzumab resistance.

BackgroundBreast carcinoma with choriocarcinomatous features (BCCF) is a rare variant of breast cancer, characterized by high expression of human chorionic gonadotropin (HCG) in cancer cells such as multinucleated syncytiotrophoblast-like giant cells. The first case of BCCF was reported in 1981 by Saigo and Rosen. Only one case of BCCF was reported to show no component of breast ductal carcinoma, and only partially cancer cells, such as multinucleated syncytiotrophoblast-like giant cells, expressed HCG in all previous BCCF cases. Here, we report the first BCCF case without any component of breast ductal carcinoma in which HCG was found to express in all cancer cells.Case presentationA 32-year-old female patient presented with a small lump in her left breast 3 years prior. The mass was clinically suspected to be breast infiltrating ductal carcinoma based on breast excisional biopsy and magnetic resonance imaging findings. Due to rupture and bleeding of the left kidney, the left kidney excisional biopsy was performed. After a retrospective analysis of the initial excised breast cancer and breast cancer metastatic to the kidney, the cancer cells were positive for HCG by immunohistochemistry, and multinucleated or mononucleated giant cells resembled syncytiotrophoblastic and cytotrophoblastic cells which could be seen in a background of poor differentiated breast carcinoma and extensive necrosis and hemorrhage in the lesion. Thus, a final diagnosis of BCCF and BCCF metastatic to the kidney was made. After combination of surgical resection (the affected left breast and left kidney wereremoved) and consecutive chemotherapy consisting of docetaxel, epirubicin, cisplatin, lobaplatin, and capecitabine, the patient achieved favorable therapeutic efficacy (the HCG level returned to normal values, the metastatic lesions in the lungs disappeared, and the survival was 37 months). Capecitabine was very efficient and highly recommended due to its superior efficacy in reducing the HCG level and eliminating the metastatic lesions in the lungs.ConclusionsThis is the first report of a rare case of BCCF without any component of breast ductal carcinoma, featured by high expression of HCG in all cancer cells. Combination of surgery and chemotherapy (especially capecitabine) achieved a favorable therapeutic efficacy.

Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with regard to mortality and prognosis, and the 5-year survival rate for all patients diagnosed with ESCC remains poor. A better understanding of the biological mechanisms of ESCC tumorigenesis and progression is of great importance to improve treatment of this disease. In this study, we demonstrated that the glutathione metabolism pathway is highly enriched in ESCC cells compared with normal esophageal epithelial cells in an in vivo mouse model. In addition, treatment with L-buthionine-sulfoximine (BSO) to deplete glutathione decreased the ESCC tumor burden in mice, thus demonstrating the critical role of glutathione metabolism in ESCC progression. BSO treatment also led to decreased cell proliferation and activation of cell apoptosis in ESCC. Finally, BSO treatment blocked NF-kB pathway activation in ESCC. Our study reveals a new pathway that regulates ESCC progression and suggests that inhibition of glutathione metabolism may be a potential strategy for ESCC treatment.