METTL14/miR-29c-3p axis drives aerobic glycolysis to promote triple-negative breast cancer progression though TRIM9-mediated PKM2 ubiquitination.

The energy metabolic rearrangement of triple-negative breast cancer (TNBC) from oxidative phosphorylation to aerobic glycolysis is a significant biological feature and can promote the malignant progression. However, there is little knowledge about the functional mechanisms of methyltransferase-like protein 14 (METTL14) mediated contributes to TNBC malignant progression. Our study found that METTL14 expression was significantly upregulated in TNBC tissues and cell lines. Silencing METTL14 significantly inhibited TNBC cell growth and invasion in vitro, as well as suppressed tumour growth. Mechanically, METTL14 was first found to activate miR-29c-3p through m6A and regulate tripartite motif containing 9 (TRIM9) to promote ubiquitination of pyruvate kinase isoform M2 (PKM2) and lead to its transition from tetramer to dimer, resulting in glucose metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to promote the progress of TNBC. Taken together, these findings reveal important roles of METTL14 in TNBC tumorigenesis and energy metabolism, which might represent a novel potential therapeutic target for TNBC.

Surgery on Metastatic Foci is a Better Strategy for Stage IV Breast Cancer Patients with only Nonregional Lymph Node Metastasis.

INTRODUCTION: Our study aims to explore whether breast cancer patients with non-regional lymph node (NRLN) metastasis benefit from surgery on distant nodes, and to determine the influencing factors affecting the prognosis of this type of patient. METHODS: Information of invasive ductal carcinoma (IDC) patients from 2004 to 2016 was extracted from the Surveillance, Epidemiology, and End Results (SEER) database and analyzed by statistical methods, including multivariate Cox regression model, chi-squared test, propensity score matching (PSM), Kaplan-Meier plot, and log-rank test. RESULTS: A total of 4236 M1 patients met the designated criteria. Among 847 patients with only NRLN metastasis who have detailed information, only 114 patients received surgery on metastatic distant lymph nodes. The Kaplan-Meier plot for overall survival (OS) showed that the prognosis of NRLN metastatic patients was superior to visceral metastasis (P < 0.0001) but similar to supraclavicular metastasis (P = 0.33). In addition, NRLN metastatic patients who underwent surgery on the NRLNs were found to have superior prognoses in terms of both OS (P = 0.041) and cancer-specific survival (P = 0.034) compared with those who did not undergo NRLN surgery. We have also demonstrated that NRLN metastatic patients who have received radiotherapy plus chemotherapy for primary tumors gain superior survival compared with those who only received chemotherapy apart from NRLN surgery. CONCLUSION: Surgery on NRLN and radiotherapy for the primary tumor improved the prognosis of NRLN metastatic patients. Thus, the classification of NRLN, especially contralateral axillary lymph node metastasis (CAM), into the M1 breast cancer stage should be reconsidered. Different locoregional treatment strategies for metastatic foci should be recommended for patients with only NRLN and patients with visceral metastasis.

Options of locoregional therapy for primary foci of breast cancer influence the rate of nonregional lymph node metastasis in N2-N3 status patients: a SEER database analysis.

OBJECTIVE: We aim to use the SEER database to discuss the effect of various surgical methods of primary foci and other influencing factors on the nonregional lymph node (NRLN) metastasis in invasive ductal carcinoma (IDC) patients. METHODS: Clinical information of IDC patients used in this study was obtained from the SEER database. The statistical analyses used included a multivariate logistic regression model, the chi-squared test, log-rank test and propensity score matching (PSM). RESULTS: 243,533 patients were included in the analysis. 94.3% of NRLN patients had a high N positivity (N3) but an equal distribution in T status. The proportion of operation type, especially BCM and MRM, differed significantly between the N0-N1 and N2-N3 groups in the NRLN metastasis group and nonmetastasis group. Age > 80 years, positive PR, modified radical mastectomy (MRM)/radical mastectomy (RM) and radiotherapy for primary tumor were shown to be protective factors for NRLN metastasis, and higher N positivity was the most significant risk factors. N2-N3 patients receiving MRM had a lower metastasis to NRLN than those receiving BCM (1.4% vs 3.7%, P < 0.001), while this relevance was not discovered in N0-N1 patients. In N2-N3 patients, a better OS was observed in MRM group than BCM group (P < 0.001). CONCLUSION: MRM exerted a protective effect on NRLN metastasis compared to BCM in N2-N3 patients but not N0-N1 patients. This implies the need for more consideration when choosing the operation methods of primary foci in patients with high N positivity.

Does Primary Tumor Resection Induce Accelerated Metastasis in Breast Cancer? A Review.

INTRODUCTION: Over a century of cumulative experimental results and clinical data have suggested that surgical procedures of primary tumors promote tumor progression and metastasis in breast cancer and other cancer patients, suggesting a potential interplay linking primary tumors and distant lesions that lead to metastasis development triggered by primary tumor removal. Such evidence may generate a departure in terms of our attitude toward the surgery. However, the reliability and prognostic benefits of tumor surgery, especially for chemotherapy-resistant patients, are indisputable. Thus, it is important to explore the mechanism underlying this surgery-induced cancer progression to guide individual clinical treatment and improve tumor control. MATERIALS AND METHODS: We conducted a comprehensive review in PubMed in October 2021 to determine the article outline. Non-English and repetitive articles were excluded. The year, topic, key findings, and opinions of each article were gathered. RESULTS: This review not only comprehensively summarizes the potential mechanisms of primary tumors interacting with the growth of metastases but also discusses whether and how surgical resection of primary lesions can trigger tumor metastasis and development. At the same time, this article also provides our understanding of clinical findings and future directions on this topic. In addition, the combination of surgery and some potentially beneficial therapeutic interventions for postoperative tumor metastasis control was also mentioned. CONCLUSIONS: There are viewpoints supporting an acceleration of metastasis after surgery for breast cancer and fundamental research on relevant therapies, although controversial. Further attention should be focused on the gap between current preclinical data and the complicated clinical therapeutic combination during surgery in metastatic breast cancer patients.

miR-140-3p/usp36 axis mediates ubiquitination to regulate PKM2 and suppressed the malignant biological behavior of breast cancer through Warburg effect.

Breast cancer is a phenomenon in which breast epithelial cells proliferate out of control under the action of various carcinogenic factors. However, the role of USP36 in breast cancer is unknown. We analyzed the expression of USP36 in breast cancer and its association with poor prognosis in breast cancer patients. The effect of USP36 on malignant biological behavior of breast cancer was verified by cell functional experiments. The upstream regulatory mechanism of USP36 was analyzed by Western blot and quantitative RT-qPCR. The influence of USP36 on the Warburg effect of breast cancer was analyzed by detecting the metabolism of cellular energy substances. We found that USP36 is highly expressed in breast tumor tissues and breast cancer cell lines. High expression of USP36 predicts poor prognosis in patients with breast cancer. Effectively reducing the expression of USP36 can significantly inhibit the proliferation, invasion and migration of breast cancer cells, and promote the apoptosis of breast cancer cells. Meanwhile, inhibiting the expression of USP36 can significantly inhibit the production of ATP, lactate, pyruvate and glucose uptake in breast cancer cells. miR-140-3p is an upstream regulator of USP36, which can partially reverse the regulatory effect of USP36 on breast cancer cells. Importantly, USP36 regulates the expression of PKM2 through ubiquitination, which plays a role in regulating the Warburg effect. We confirmed that miR-140-3p regulates the expression of USP36, which mediates ubiquitination and regulates the expression of PKM2, and regulates the malignant biological behavior of breast cancer through the energy metabolism process.

DNMT3B and TET1 mediated DNA methylation of LATS1 regulates BC progression via hippo signaling pathway.

BACKGROUND: Large tumor suppressor gene 1 (LATS1) is one of the key proteins in the Hippo signaling pathway, which plays a role in inhibiting tumor progression, but its anti-tumor role in tumors is inhibited. Nevertheless, the specific molecular mechanism of its role in breast cancer (BC) are still unclear. METHODS: The expression of LATS1 in BC was detected by RT-qCR and WB. The biological effect of LATS1 on BC was verified in vitro and in vivo. DNA methylation sequencing and MSP were used to detect the effect of DNMT3B and TET1 on LATS1 methylation. Analysis of the effect of DNMT3B and TET1 on the biological behavior of BC cells via LATS1 by cell function experiment. RESULTS: Results indicated that the expression of LATS1 is lower in BC tumor tissues and BC cell lines. low LATS1 expression BC patients have a shorter overall survival. Increasing LATS1 expression can inhibit the proliferation, migration and invasion of BC. LATS1 found to have high DNA methylation changes in the promoter region. Moreover, DNMT3B was increased in BC tissues, and DNA demethylase TET1 was decreased in BC tissues. Furthermore, DNMT3B and TET1 regulate the methylation of LATS1, and methylation of LATS1 inactivates Hippo signaling pathway. CONCLUSION: Our results indicate that the methylation of LATS1 is regulated by DNMT3B and TET1 and regulates its protein expression and the function of Hippo signaling pathway.

TRIM35 ubiquitination regulates the expression of PKM2 tetramer and dimer and affects the malignant behaviour of breast cancer by regulating the Warburg effect.

Breast cancer has become the leading cause of death in females. After comprehensive treatment, the lives of patients are still threatened by tumor metastasis and recurrence. Therefore, there is an urgent requirement to find an effective treatment target for breast cancer. Tripartite motif­containing 35 (TRIM35) is a ubiquitin ligase that has an important role in the recurrence and metastasis of malignant tumors. However, the role of TRIM35 in breast cancer has thus far remained elusive. The expression of TRIM35 was examined in a bioinformatics database and the effects of TRIM35 on the malignant biological behavior of breast cancer were analyzed by Cell Counting Kit­8, cell migration and invasion assays, flow cytometry and nude mouse xenograft experiments. It was determined that TRIM35 was downregulated in breast cancer tumor tissues and cell lines. Patients with low TRIM35 expression had shorter overall survival. Functional assays revealed that overexpression of TRIM35 inhibited the proliferation, migration and invasion, and promoted apoptosis of breast cancer cells. Furthermore, overexpression of TRIM35 was able to inhibit the Warburg effect in breast cancer cells. Mechanistic analyses indicated that TRIM35 regulates the transition of tetramers and dimers of pyruvate kinase M2 (PKM2) through ubiquitination and thereby affects the Warburg effect. In conclusion, the present results indicated that TRIM35 regulates the tetramer and dimer transition of PKM2 through ubiquitination and affects the malignant biological behavior of breast cancer by modulating the Warburg effect.