Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis and radiotherapy resistance through JNK pathway.

BACKGROUND: Despite radiotherapy ability to significantly improve treatment outcomes and survival in triple-negative breast cancer (TNBC) patients, acquired resistance to radiotherapy poses a serious clinical challenge. Protein disulfide isomerase exists in endoplasmic reticulum and plays an important role in promoting protein folding and post-translational modification. However, little is known about the role of protein disulfide isomerase family member 4 (PDIA4) in TNBC, especially in the context of radiotherapy resistance. METHODS: We detected the presence of PDIA4 in TNBC tissues and paracancerous tissues, then examined the proliferation and apoptosis of TNBC cells with/without radiotherapy. As part of the validation process, xenograft tumor mouse model was used. Mass spectrometry and western blot analysis were used to identify PDIA4-mediated molecular signaling pathway. RESULTS: Based on paired clinical specimens of TNBC patients, we found that PDIA4 expression was significantly higher in tumor tissues compared to adjacent normal tissues. In vitro, PDIA4 knockdown not only increased apoptosis of tumor cells with/without radiotherapy, but also decreased the ability of proliferation. In contrast, overexpression of PDIA4 induced the opposite effects on apoptosis and proliferation. According to Co-IP/MS results, PDIA4 prevented Tax1 binding protein 1 (TAX1BP1) degradation by binding to TAX1BP1, which inhibited c-Jun N-terminal kinase (JNK) activation. Moreover, PDIA4 knockdown suppressed tumor growth xenograft model in vivo, which was accompanied by an increase in apoptosis and promoted tumor growth inhibition after radiotherapy. CONCLUSIONS: The results of this study indicate that PDIA4 is an oncoprotein that promotes TNBC progression, and targeted therapy may represent a new and effective anti-tumor strategy, especially for patients with radiotherapy resistance.

INSM1 promotes breast carcinogenesis by regulating C-MYC.

Insulinoma-associated protein-1 (INSM1), which is highly expressed in various neuroendocrine tumors, functions as a zinc finger transcription factor capable of regulating the biological behavior of tumor cells. However, its specific role in breast cancer remains unclear. This study aims to investigate the role and mechanism of INSM1 in breast cancer. A total of 158 cohorts were recruited to examine the expression of INSM1 in breast cancer tissues and their corresponding adjacent normal tissues using immunohistochemistry. Follow-up data, along with clinical and pathological information, were collected to analyze the correlation between INSM1 expression and survival outcomes in breast cancer patients. Additionally, we investigated the impact of INSM1 on breast cancer cell proliferation, migration, and aggregation. To further explore the regulatory effect of INSM1 knockdown on breast cancer tumor growth, we utilized a xenograft mouse model. The results revealed that INSM1 was significantly overexpressed in breast cancer patients and correlated with prognosis. Knockdown of INSM1 notably impaired the malignant biological effects of breast cancer cells and inhibited the growth of xenograft tumors in nude mice. Importantly, our data also suggests an interaction between INSM1 and S-phase kinase-associated protein 2 (SKP2), which in turn regulates C-MYC, thereby affecting the p-ERK pathway. Our study provides the first evidence demonstrating the contribution of INSM1 to tumor formation and growth in breast cancer. Furthermore, we found that INSM1 positively regulates C-MYC and the p-ERK pathway by interacting with SKP2 during breast cancer development. Collectively, these findings highlight INSM1 as a promising target for breast cancer treatment.

Study on the Relationship Between Differentially Expressed Proteins in Breast Cancer and Lymph Node Metastasis.

INTRODUCTION: Lymph node metastasis is a cause of poor prognosis in breast cancer. Mass spectrometry-based proteomics aims to map the protein landscapes of biological samples and profile tumors more comprehensively. Here, proteomics was employed to identify differentially expressed proteins (DEPs) that were associated with lymph node metastasis. METHODS: Tandem mass tag (TMT) quantitative proteomic approaches were applied for extensive profiling of conditioned medium of MDA-MB-231 and MCF7 cell lines and serums of patients who did or did not have lymph node metastasis, and DEPs were analyzed by bioinformatics. Furthermore, potential secreted or membrane proteins MUC5AC, ITGB4, CTGF, EphA2, S100A4, PRDX2, and PRDX6 were selected for verification in 114 tissue microarray samples of breast cancer using the immunohistochemical method. The relevant data was analyzed and processed by independent sample t test, chi-square test, or Fisher's exact test using SPSS 22.0 software. RESULTS: In the conditioned medium of MDA-MB-231 cell lines, 154 proteins were upregulated, while 136 were downregulated compared to those of MCF7. In the serum of patients with breast cancer and lymph node metastasis, 17 proteins were upregulated, and 5 proteins were downregulated compared to those without lymph node metastasis. Furthermore, according to tissue verification, CTGF, EphA2, S100A4, and PRDX2 were associated with breast cancer lymph node metastasis. CONCLUSION: Our study provides a new perspective for the understanding of the role of DEPs (especially CTGF, EphA2, S100A4, and PRDX2) in the development and metastasis of breast cancer. They could become potential diagnostic and prognostic biomarkers and therapeutic targets.

Effectiveness and Safety of Zercepac and Reference Trastuzumab in the Neoadjuvant Setting for Early-Stage Breast Cancer: A Retrospective Cohort Study.

Aim: Since the high cost of reference trastuzumab limits its clinical application, this study aimed to compare the effectiveness and safety of the Zercepac and reference product trastuzumab in neoadjuvant therapy for HER2-positive breast cancer. Methods: This study retrospectively collected clinical data of patients with early-stageHER2-positive breast cancer, who received trastuzumab, pertuzumab, docetaxel, and platinum as neoadjuvant therapy from November 2020 to July 2021. Patients were divided into the Zercepac and reference trastuzumab groups. Reduction in tumor size, clinical response based on RECIST1.1 criteria, pathological complete response (pCR), and adverse events (AEs) were evaluated. Multivariate logistic regression analyses were used to adjust confounders. Results: A total of 105 patients were included in the study, among them, 65 were in the Zercepac group and 40 were in the reference trastuzumab group. The percentage of tumor shrinkage from baseline was comparable between the Zercepac and reference trastuzumab group (47.6 ± 18.6% vs. 43.0 ± 19.9%, p = 0.235). Clinical partial response rate was similar between the two groups (81.5% vs. 70.0%, p = 0.172). There were 28 cases of pCR (70.0%) in the reference trastuzumab group and 46 cases of pCR (70.8%) in the Zercepac group (p = 0.933). The choice of Zercepac or reference trastuzumab was not significantly associated with pCR (OR = 0.96, 95%CI: 0.41-2.28, p = 0.933). Adverse events (AEs) were observed in all patients, and the incidence of ≥3 grade AEs was comparable between the two groups (81.5% vs. 70.0%, p = 0.172). Conclusion: Zercepac has similar effectiveness and safety profile compared with reference trastuzumab in neoadjuvant therapy, which provides treatment options for patients with HER2-positive breast cancer.

Breast cancer cell-derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function.

Evidence suggests that increased microRNA-155 (miR-155) expression in immune cells enhances antitumor immune responses. However, given the reported association of miR-155 with tumorigenesis in various cancers, a debate is provoked on whether miR-155 is oncogenic or tumor suppressive. We aimed to interrogate the impact of tumor miR-155 expression, particularly that of cancer cell-derived miR-155, on antitumor immunity in breast cancer. We performed bioinformatic analysis of human breast cancer databases, murine experiments, and human specimen examination. We revealed that higher tumor miR-155 levels correlate with a favorable antitumor immune profile and better patient outcomes. Murine experiments demonstrated that miR-155 overexpression in breast cancer cells enhanced T cell influx, delayed tumor growth, and sensitized the tumors to immune checkpoint blockade (ICB) therapy. Mechanistically, miR-155 overexpression in breast cancer cells upregulated their CXCL9/10/11 production, which was mediated by SOCS1 inhibition and increased phosphorylated STAT1 (p-STAT1)/p-STAT3 ratios. We further found that serum miR-155 levels in breast cancer patients correlated with tumor miR-155 levels and tumor immune status. Our findings suggest that high serum and tumor miR-155 levels may be a favorable prognostic marker for breast cancer patients and that therapeutic elevation of miR-155 in breast tumors may improve the efficacy of ICB therapy via remodeling the antitumor immune landscape.

MEX3A promotes development and progression of breast cancer through regulation of PIK3CA.

Breast cancer has been identified as the most common malignant tumors among women and the morbidity of breast cancer is still increasing rapidly. MEX3A possesses important functions in the regulation of mRNAs and may be involved in a variety of human diseases including cancer, whose relationship with breast cancer is still not clear. In this study, MEX3A was identified as a potential promotor in breast cancer, whose expression was strongly higher in breast cancer tissues than normal tissues. The in vitro experiments showed that MEX3A is capable of promoting the development of breast cancer through stimulating cell proliferation, inhibiting cell apoptosis, arresting cell cycle and promoting cell migration. The functions of MEX3A were also verified in vivo. Furthermore, a combination of genechip analysis and Ingenuity pathway analysis (IPA) identified PIK3CA as a potential downstream target of MEX3A, knockdown of which executes similar inhibitory effects on breast cancer and could alleviate MEX3A-induced progression of breast cancer. In conclusion, our study unveiled, as the first time, MEX3A as a tumor promotor for breast cancer, whose function was carried out probably through the regulation of PIK3CA.