HDAC7 inhibits cell proliferation via NudCD1/GGH axis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. In the absence of effective molecular markers for TNBC, there is an urgent clinical need for promising therapeutic target for TNBC. Histone deacetylases (HDACs), key regulators for chromatin remodeling and gene expression, have been suggested to play critical roles in cancer development. However, little is known ~the functions and implications of HDACs in TNBC treatment in the future. By analyzing the expression and prognostic significance of HDAC family members in TNBC through TCGA and METABRIC databases, HDAC7 was found to be downregulated in TNBC samples and the survival of patients with lower expression of HDAC7 was shorter. Furthermore, HDAC7 was negatively associated with NudC domain containing 1 (NudCD1) and γ-glutamyl hydrolase (GGH). Loss of NudCD1 or GGH predicted improved overall survival time (OS) of patients with TNBC. In vitro experiments showed that silencing of HDAC7 enhanced TNBC cell proliferation, while overexpression HDAC7 inhibited TNBC cell proliferation. The results of functional experiments confirmed that HDAC7 negatively modulated GGH and NudCD1 expression. Furthermore, decrease of NudCD1 or GGH inhibited cell proliferation. Notably, the HDAC7-NudCD1/GGH axis was found to be associated with NK cell infiltration. Overall, the present study revealed a novel role of HDAC7-NudCD1/GGH axis in TNBC, which might provide a promising treatment strategy for patients with TNBC.

Assessing real-world safety concerns of Sacituzumab govitecan: a disproportionality analysis using spontaneous reports in the FDA adverse event reporting system.

Aim: The aim of this study was to identify potential safety concerns associated with Sacituzumab Govitecan (SG), an antibody-drug conjugate targeting trophoblastic cell-surface antigen-2, by analyzing real-world safety data from the largest publicly available worldwide pharmacovigilance database. Methods: All data obtained from the FDA Adverse Event Reporting System (FAERS) database from the second quarter of 2020 to the fourth quarter of 2022 underwent disproportionality analysis and Bayesian analysis to detect and assess the adverse event signals of SG, considering statistical significance when the lower limit of the 95% CI >1, based on at least 3 reports. Results: Total of 1072 cases were included. The main safety signals were blood and lymphatic system disorders [ROR(95CI)=7.23 (6.43-8.14)], gastrointestinal disorders [ROR(95CI)=2.01 (1.81-2.22)], and relative infection adverse events, such as neutropenic sepsis [ROR(95CI)=46.02 (27.15-77.99)] and neutropenic colitis [ROR(95CI)=188.02 (120.09-294.37)]. We also noted unexpected serious safety signals, including large intestine perforation [ROR(95CI)=10.77 (3.47-33.45)] and hepatic failure [ROR(95CI)=3.87 (1.45-10.31)], as well as a high signal for pneumonitis [ROR(95CI)=9.93 (5.75-17.12)]. Additionally, age sub-group analysis revealed that geriatric patients (>65 years old) were at an increased risk of neutropenic colitis [ROR(95CI)=282.05 (116.36-683.66)], neutropenic sepsis [ROR(95CI)=101.11 (41.83-244.43)], acute kidney injury [ROR(95CI)=3.29 (1.36-7.94)], and atrial fibrillation [ROR(95CI)=6.91 (2.86-16.69)]. Conclusion: This study provides crucial real-world safety data on SG, complementing existing clinical trial information. Practitioners should identify contributing factors, employ monitoring and intervention strategies, and focus on adverse events like neutropenic sepsis, large intestine perforation, and hepatic failure. Further prospective studies are needed to address these safety concerns for a comprehensive understanding and effective management of associated risks.

Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors.

CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2- breast cancer patients. Nevertheless, the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest. Here, we show that the palbociclib-resistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis. Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib. Furthermore, PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells, leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation. Targeting PI3K/mTOR pathway with a specific PI3Kα inhibitor (BYL719) or an mTOR inhibitor (everolimus) reduced the protein levels of Cyclin D1 and CDK4, and restored the sensitivity to palbociclib. The tumor samples expressed significantly higher levels of Cyclin D1, CDK4, p-AKT and p-4E-BP1 after progression on palbociclib treatment. In conclusion, our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors, which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.

Global Trend in Research and Development of CDK4/6 Inhibitors for Clinical Cancer Therapy: A Bibliometric Analysis.

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors are frequently used anti-cancer agents in hormone receptor-positive breast cancers. This study assessed the course of research and development (R&D) for CDK4/6 inhibitors in terms of publications over the past two decades. Methods: The Web of Science (WOS) and PubMed databases were searched to identify publications related to research on CDK4/6 inhibitors since 2001. The VOS Viewer software was used to analyze co-occurring keywords to stratify the publication data and collaborations in research. Results: There were 1395 publications related to research on CDK4/6 inhibitors since 2001. Eight of the top 10 institutions originated from the USA and the other two were a Swiss Pharmaceutical Company and French Research Institute. Bardia A, the first author for some of the articles published in the USA, was the most prolific with 25 publications. The journal with the most publications was Cancer Res with 162 publications. Basic research comprised six of the 10 most frequently cited publications and the rest consisted of three reviews and a clinical trial. The most common keywords for publications since 2011 were "palbociclib", "abemaciclib", "ribociclib" and "double blind", indicating the successful development of CDK4/6 inhibitors as anticancer drugs. Conclusions: This study provides a comprehensive review of the CDK4/6 inhibitors R&D history. The data imply that drug development in this field is a decade-long process and clinical trials have been performed before clinical applications. Thereafter, research was conducted on the adverse effects and drug resistance associated with the inhibitors.

LIN9 confers paclitaxel resistance in triple negative breast cancer cells by upregulating CCSAP.

LIN9 functions to regulate cell mitotic process. Dysregulation of LIN9 expression is associated with development of human cancers. In this study we assessed the association of LIN9 expression with paclitaxel resistance and clarified the underlying mechanisms for the first time. LIN9 expression in breast cancer tissues was retrieved from publicly available online databases and statistically analyzed. Human TNBC cell lines MDA-MB-231 and MDA-MB-468 and their corresponding paclitaxel-resistant sublines 231PTX and 468PTX were used to assess the expression of LIN9 by qRT-PCR and Western blot, cell growth by cell counting, cell viability by MTS assay, and cell apoptosis by flow cytometry. The data showed that high LIN9 expression in breast cancer patients receiving chemotherapy was related to poor overall survival (OS). LIN9 expression was upregulated in paclitaxel-resistant TNBC cells compared to their parental cells. Knockdown of LIN9 or treatment of paclitaxel-resistant TNBC cells with a bromo- and extra-terminal domain inhibitor (BETi) JQ1 which also decreased LIN9 expression enhanced the sensitivity of paclitaxel-resistant TNBC cells to paclitaxel. Mechanistically, decreased LIN9 in resistant cell lines reduced tumor cell viability, promoted multinucleated cells formation and induced tumor cell apoptosis, potentially by directly regulating microtubule-binding protein CCSAP. In conclusion, high LIN9 expression contributed to poor clinical outcomes and paclitaxel resistance in TNBC and BETi, targeting LIN9 expression, could be a reversible drug for PTX-resistant TNBC patients.

LncRNA DILA1 inhibits Cyclin D1 degradation and contributes to tamoxifen resistance in breast cancer.

Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Here, we identify a lncRNA, DILA1, which interacts with Cyclin D1 and is overexpressed in tamoxifen-resistant breast cancer cells. Mechanistically, DILA1 inhibits the phosphorylation of Cyclin D1 at Thr286 by directly interacting with Thr286 and blocking its subsequent degradation, leading to overexpressed Cyclin D1 protein in breast cancer. Knocking down DILA1 decreases Cyclin D1 protein expression, inhibits cancer cell growth and restores tamoxifen sensitivity both in vitro and in vivo. High expression of DILA1 is associated with overexpressed Cyclin D1 protein and poor prognosis in breast cancer patients who received tamoxifen treatment. This study shows the previously unappreciated importance of post-translational dysregulation of Cyclin D1 contributing to tamoxifen resistance in breast cancer. Moreover, it reveals the novel mechanism of DILA1 in regulating Cyclin D1 protein stability and suggests DILA1 is a specific therapeutic target to downregulate Cyclin D1 protein and reverse tamoxifen resistance in treating breast cancer.

Circulating Tumor DNA Predicts the Response and Prognosis in Patients With Early Breast Cancer Receiving Neoadjuvant Chemotherapy.

PURPOSE: Many patients with breast cancer still relapse after curative treatment. How to identify the ones with high relapse risk remains a critical problem. Circulating tumor DNA (ctDNA) has recently become a promising marker to monitor tumor burden. Whether ctDNA can be used to predict the response and prognosis in patients with breast cancer receiving neoadjuvant chemotherapy (NAC) is unknown. Our study aimed to evaluate the clinical value of the presence and dynamic change of ctDNA to predict the tumor response and prognosis in patients with breast cancer treated with NAC. MATERIALS AND METHODS: Fifty-two patients with early breast cancer who underwent NAC were prospectively enrolled. Serial plasma samples before, during, and after NAC and paired tumor biopsies were harvested and subjected to deep targeted sequencing using a large next-generation sequencing panel that covers 1,021 cancer-related genes. RESULTS: Positive baseline ctDNA was detected in 21 of 44 patients before NAC. Most patients with positive ctDNA had one or more mutations confirmed in paired primary tumor. The ctDNA level after 2 cycles of NAC was predictive of local tumor response after all cycles of NAC (area under the curve, 0.81; 95% CI, 0.61 to 1.00). ctDNA tracking during NAC outperformed imaging in predicting the overall response to NAC. More importantly, positive baseline ctDNA is significantly associated with worse disease-free survival (P = .011) and overall survival (P = .004) in patients with early breast cancer, especially in estrogen receptor-negative patients. CONCLUSION: Our study demonstrated that ctDNA can be used to predict tumor response to NAC and prognosis in early breast cancer, providing information to tailor an individual's therapeutic regimen.

Non-invasive analysis of tumor mutation profiles and druggable mutations by sequencing of cell free DNA of Chinese metastatic breast cancer patients.

BACKGROUND: Metastatic breast cancer (MBC) remains an incurable disease worldwide. Tumor gene mutations have evolved and led to drug resistance in the treatment course of MBC. However, data on the mutation profiles and druggable genomic alterations of MBC remain limited, particularly among Chinese patients. Our study aimed to depict the mutation profiles and identify druggable mutations in circulating tumor DNA (ctDNA) in Chinese MBC patients. METHODS: Targeted deep sequencing of a 1021-gene panel was performed on 17 blood samples and 5 available tissue samples from 17 Chinese MBC patients. RESULTS: We identified 60 somatic mutations in 17 blood samples (sensitivity 100%). Somatic mutations were identified in the blood samples of all patients, and 41.18% (7/17) of patients harbored at least one druggable mutation. A high ctDNA level in plasma is associated with shorter progression-free survival. CONCLUSION: Targeted deep sequencing of cell free DNA is a highly sensitive, noninvasive method to depict tumor mutation profiles, identify druggable mutations in MBC, and predict patient outcome. Our study shed light on the utility of ctDNA as noninvasive "liquid biopsy" in the management of MBC.

Discovery of CCL18 antagonist blocking breast cancer metastasis.

Our previous studies have proved that CCL18 is the most secreted chemokine in breast cancer microenvironment by tumor associated macrophages (TAMs). CCL18 promotes breast cancer invasiveness by binding to its cognate receptor PITPNM3 and activating the downstream signaling pathways. The high level of CCL18 in serum or tumor stroma is associated with tumor metastasis and poor patients overall survival. In this study, we identify an effective small molecular compound (SMC) to antagonize the effect of CCL18. We screen more than 1000 SMCs from Sun Yat-sen University SMC library and select 15 top scored SMCs by using computer-aided virtual screening based on the structure of CCL18. Then in vitro cell migration assay narrows down the selected 15 SMCs to the most effective SMC-21598. We find 10 µM SMC-21598 significantly inhibits CCL18-induced breast cancer cells adherence, invasiveness, and migration. Our further surface plasmon resonance (SPR), fluorescence spectroscopy and isothermal titration calorimetry (ITC) assays reveal that SMC-21598 binds tightly to CCL18, which blocks the binding of CCL18 with its receptor PITPNM3. The in vivo animal experiments show that SMC-21598 doesn't significantly affect xenografts growth, but inhibits lung metastasis. Our study provides a potential lead compound to antagonize CCL18 function. It would be of great significance to develop SMC drugs to ameliorate breast cancer metastasis and prolong patients' survival.

Long non-coding RNA CRALA is associated with poor response to chemotherapy in primary breast cancer.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women, and has become the second leading cause of cancer death among women worldwide. Chemoresistance has become an important problem in breast cancer clinics. The identification of new mechanisms affecting chemosensitivity is of great clinical value for the treatment of breast cancer. METHODS: The expression levels of chemoresistance-associated long non-coding RNA (CRALA), a newly discovered long non-coding RNA, were measured by quantitative real time-PCR in 79 pre-treatment biopsied primary breast cancer samples. Small interfering RNAs were used to knockdown CRALA expression. The effect of CRALA on chemosensitivity was evaluated using cell growth assay. RESULTS: Non-responding tumors (poor response to chemotherapy, 32 samples) had fourfold higher CRALA expression than responding tumors (good response to chemotherapy, 47 samples). CRALA is upregulated in chemoresistant breast cancer cell lines compared to their parental lines. Silencing of CRALA in chemoresistant breast cancer cells resensitizes the cells to chemotherapy in vitro. Furthermore, univariate and multivariate analysis showed that higher CRALA expression was significantly associated with poor prognosis in 144 breast cancer patients. CONCLUSION: The study findings indicate that CRALA expression may be an important biomarker for predicting the clinical response to chemotherapy and prognosis in breast cancer patients. It is possible to target CRALA to reverse chemoresistance in breast cancer patients.