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Background: Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large‐scale Chinese BC patients. Methods: BC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. Results: A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high‐risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high‐risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non‐BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non‐BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. Conclusions: Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non‐BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies. [ABSTRACT FROM AUTHOR]

Background: Current guidelines recommend adjuvant chemotherapy for patients with small, lymph node-negative, triple-negative breast cancer (TNBC) measuring >5 mm (T1b disease), but clinical evidence to support this recommendation is lacking. Thus, the current study aimed to evaluate the survival benefit of adjuvant chemotherapy in patients with T1N0M0 (measuring ≤2 cm) TNBC with different tumor sizes.Methods: The authors retrospectively evaluated consecutive patients with pT1N0M0 TNBC who were diagnosed between 2000 and 2016 at Sun Yat-Sen University Cancer Center. For the meta-analysis, electronic medical databases were searched for all relevant studies regarding the effect of adjuvant chemotherapy on the target population.Results: Of the 351 enrolled patients, 309 (88%) received adjuvant chemotherapy and 42 patients (12%) did not. The distribution by T classification was T1a in 19 patients (5.4%), T1b in 67 patients (19.1%), and T1c in 265 patients (75.5%). Adjuvant chemotherapy significantly improved recurrence-free survival (RFS) in the patients with T1c disease, but not those with T1b and T1a disease. Meanwhile, there was no difference in RFS noted according to the chemotherapy regimen among patients with T1c disease. Seven eligible studies comprising 1525 patients with T1N0M0 (941 with T1a/bN0M0) were included in the meta-analysis. The meta-analysis demonstrated that adjuvant chemotherapy significantly reduced the rate of disease recurrence for patients with T1a/b disease as a group, but the population driving that was only patients with T1b disease, not those with T1a disease.Conclusions: Although the retrospective analysis demonstrated a survival benefit of adjuvant chemotherapy only for patients with T1cN0 TNBC, the meta-analysis showed it also is beneficial for individuals with T1bN0 TNBC. For patients with T1cN0M0 TNBC, less intensive chemotherapy regimens achieve an excellent survival outcome similar to that of intensive anthracycline and taxane combination chemotherapy. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with high proliferative and metastatic phenotypes. CDCA7, a new member of the cell division cycle associated family of genes, is involved in embryonic development and dysregulated in various types of human cancer. However, the biological role and molecular mechanism of CDCA7 in TNBC have not been defined. Herein, we found that CDCA7 was preferentially and markedly expressed in TNBC cell lines and tissues. High expression of CDCA7 was associated with metastatic relapse status and predicted poorer disease‐free survival in patients with TNBC. We observed that CDCA7 silencing in TNBC cell lines effectively impaired cell proliferation, invasion and migration in vitro. Importantly, depletion of CDCA7 strongly reduced the tumorigenicity and distant colonization capacities of TNBC cells in vivo. Furthermore, CDCA7 increased the expression of EZH2, a marker of aggressive breast cancer that is involved in tumor progression, by enhancing the transcriptional activity of its promoter. This increase in EZH2 expression was essential for the CDCA7‐mediated effects on TNBC progression. Finally, our immunohistochemical analysis revealed that the CDCA7/EZH2 axis was clinical relevant. These findings suggest CDCA7 plays a crucial role in TNBC progression by transcriptionally upregulating EZH2 and might be a potential prognostic factor and therapeutic target in TNBC. What's new? Cell division cycle‐associated 7 (CDCA7) protein, a c‐Myc‐interacting transcriptional regulator, is overexpressed in breast cancer, where it potentially impacts tumor development. The relevance of CDCA7 in breast cancer, however, is unknown. Here, analyses reveal marked CDCA7 upregulation in tissues from patients with highly aggressive triple‐negative breast cancer (TNBC). High CDCA7 expression was associated with metastatic relapse status and predicted poor disease‐free survival in TNBC patients. Meanwhile, in vitro silencing of CDCA7 inhibited TNBC cell proliferation and triggered TNBC cell death. Additional experiments indicate that CDCA7 transcriptionally upregulates the epigenetic modifier EZH2, thereby promoting TNBC cell aggressiveness and metastasis. [ABSTRACT FROM AUTHOR]

Abstract: Argonaute/Piwi proteins can regulate gene expression via RNA degradation and translational regulation using small RNAs as guides. They also promote the establishment of suppressive epigenetic marks on repeat sequences in diverse organisms. In mice, the nuclear Piwi protein MIWI2 and Piwi‐interacting RNAs (piRNAs) are required for DNA methylation of retrotransposon sequences and some other sequences. However, its underlying molecular mechanisms remain unclear. Here, we show that piRNA‐dependent regions are transcribed at the stage when piRNA‐mediated DNA methylation takes place. MIWI2 specifically interacts with RNAs from these regions. In addition, we generated mice with deletion of a retrotransposon sequence either in a representative piRNA‐dependent region or in a piRNA cluster. Both deleted regions were required for the establishment of DNA methylation of the piRNA‐dependent region, indicating that piRNAs determine the target specificity of MIWI2‐mediated DNA methylation. Our results indicate that MIWI2 affects the chromatin state through base‐pairing between piRNAs and nascent RNAs, as observed in other organisms possessing small RNA‐mediated epigenetic regulation. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor, and the HER2 receptor; it is highly proliferative and becomes the deadliest forms of breast cancer. Effective prognostic methods and therapeutic targets for TNBC are required to improve patient outcomes. Here, we report that acidic nuclear phosphoprotein 32 family member E (ANP32E), which promotes cell proliferation in mammalian development, is highly expressed in TNBC cells compared to other types of breast cancer. High expression of ANP32E correlates significantly with worse overall survival (OS; P < 0.001) and higher risks of disease recurrence (P < 0.001) in patients with TNBC. Univariate and multivariate Cox‐regression models show that ANP32E is an independent prognostic factor in TNBC. Furthermore, we discovered that ANP32E promotes tumor proliferation in vitro by inducing G1/S transition, and ANP32E inhibition suppresses tumor formation in vivo. By examining the expression of E2F1, cyclin E1, and cyclin E2, we discovered that ANP32E promotes the G1/S transition by transcriptionally inducing E2F1. Taken together, our study shows that ANP32E is an efficient prognostic marker, and it promotes the G1/S transition and induces tumorigenesis of TNBC cells by transcriptionally inducing E2F1. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, with a high incidence of distant metastasis; however, the underlying mechanism for this frequent recurrence remains unclear. Herein, we show that synaptopodin-2 (SYNPO2), a putative tumour suppressor in aggressive cancer, is frequently downregulated in TNBC by methylation of the promoter of SYNPO2. Low expression levels of SYNPO2 correlated significantly with 5-year metastatic relapse, and predicted poorer prognosis in breast cancer patients. Reintroduction of SYNPO2 inhibited the invasion and spontaneous metastasis of TNBC cells in vivo. Strikingly, downregulation of SYNPO2 is essential for the maintenance of stem cell-like properties in TNBC cells, leading to efficient distant colonization and metastasis outgrowth. Moreover, we demonstrate that SYNPO2 inhibits the activities of YAP and TAZ by stabilizing LATS2 protein, and transduction of YAP-S127A abrogates the repressive role of SYNPO2 in metastasis. Finally, immunohistochemical (IHC) analysis of breast cancer patient specimens indicated that the SYNPO2-LATS2-YAP axis is clinically relevant. These findings uncover a suppressive role of SYNPO2 in TNBC metastasis via inhibition of YAP/TAZ, and suggest that SYNPO2 might provide a potential prognosis marker and novel therapeutic strategy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy in females. The presence of cancer stem cells ( CSCs) is the main cause of local and distant tumour recurrence and is associated with poor outcome in breast cancer. However, the molecular mechanisms underlying the maintenance of CSCs remain largely unknown. This study demonstrates that prostate tumour overexpressed-1 ( PTOV1) enhances the CSC population and augments the tumourigenicity of breast cancer cells both in vitro and in vivo. Moreover, PTOV1 suppresses transcription of Dickkopf-1 ( DKK1) by recruiting histone deacetylases and subsequently reducing DKK1 promoter histone acetylation, followed by activation of Wnt/β-catenin signalling. Restoration of DKK1 expression in PTOV1-overexpressing cells counteracts the effects of PTOV1 on Wnt/β-catenin activation and the CSC population. Collectively, these results suggest that PTOV1 positively regulates the Wnt/β-catenin signalling pathway and enhances tumourigenicity in breast cancer; this novel mechanism may represent a therapeutic target for breast cancer. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Breast cancer research and treatment by different subtypes is an inevitable trend. We investigated the clinicopathologic features and outcomes of different breast cancer subtypes in Southern China. A total of 5809 patients with invasive ductal carcinomas were identified. Immunohistochemical (IHC) markers for estrogen receptor ( ER), progesterone receptor ( PR), Her2/neu, and Ki-67 proliferation index were used to classify cases into five molecular subtypes. Clinicopathologic characteristics and survival rates were analyzed retrospectively. Of all patients, 31.1% were luminal A subtype, 30.4% luminal B (high Ki-67), 13.1% luminal B (Her2/neu+), 9.0% Her2/neu and 16.5% triple negative subtype. Luminal B (high Ki-67) presented primarily in premenopausal patients with the lowest average age (43.0 years). Her2/neu positive tumors were more closely associated with aggressive features including increased tumor size, positive lymph node status and lymphvascular invasion ( LVI). Triple negative subtype was characterized by poorer histologic grade. Her2/neu positive cases had presented the worst 5-year disease-free survival ( DFS) and overall survival ( OS). Multivariate analyses of OS and DFS suggested that there were different negative prognostic factors for the five subtypes. The benefit of the cyclophosphamide, methotrexate, and 5-fluorouracil (5FU) (CMF) regimen was equal to that of anthracycline-based and Taxane-based regimens for patients with luminal A subtype and triple negative subtype, but inferior to anthracycline-based and Taxane-based regimens for those with two luminal B subtypes and Her2/neu subtype. The prognostic significance of traditional markers may differ among subtypes. This study revealed the distinct clinicopathologic characteristics, systemic therapy benefits, prognostic factors and survival rate among different breast cancer subtypes. [ABSTRACT FROM AUTHOR]