Tucidinostat Plus Exemestane as a Neoadjuvant in Early-Stage, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

BACKGROUND: To assess the efficacy and safety of tucidinostat plus exemestane as a neoadjuvant strategy in early-stage breast cancer. METHODS: This prospective, open-label, single-arm phase II trial enrolled patients with stage II-III breast cancer with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Eligible patients received tucidinostat plus exemestane, and then breast-conserving surgery (BCS) or modified radical mastectomy. RESULTS: Among 20 enrolled patients, 3 of them achieved preoperative endocrine prognostic index (PEPI) score of 0. Additionally, complete cell cycle arrest was observed in 7, radiologic objective response rate in 10, and disease control rate in 20 patients, pathological complete response in 1 patient, and 5 patients performed BCS. Ki67 suppression from baseline to surgery was observed in 17 of patients, with the Ki67 change ratio of -73.5%. Treatment-emergent adverse event included neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypoalbuminemia, aspartate aminotransferase elevation, glutamyl transpeptidase elevation, anemia, and alanine aminotransferase elevation. CONCLUSIONS: Despite the rate of PEPI score 0 was not high, tucidinostat plus exemestane as a neoadjuvant therapy might be well tolerated and showed promising clinical responses in patients with early hormone receptor-positive, HER2-negative breast cancer. To clarify the safety and efficacy of this strategy, further investigation is warranted. CLINICAL TRIAL REGISTRATION: ChiCTR2100046678.

Real-world data on neoadjuvant chemotherapy with dual-anti HER2 therapy in HER2 positive breast cancer.

BACKGROUND: Neoadjuvant chemotherapy with dual-targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)-positive breast cancer. Although the dual-targeted therapy has significantly improved the pathological complete response (pCR) rate, further investigation is needed to identify biomarkers that predict the response to neoadjuvant therapy. METHODS: This retrospective study analyzed 353 patients with HER2-positive breast invasive ductal carcinoma. The correlation between clinicopathological factors and pCR rate was evaluated. A nomogram was constructed based on the results of the multivariate logistic regression analysis to predict the probability of pCR. RESULTS: The breast pCR (b-pCR) rate was 56.1% (198/353) and the total pCR (t-pCR) rate was 52.7% (186/353). Multivariate analysis identified ER status, PR status, HER2 status, Ki-67 index, and neoadjuvant chemotherapy regimens as independent indicators for both b-pCR and t-pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.73 (95% CI: 0.68-0.78). According to the nomogram, the t- pCR rate was highest in the ER-PR- HER2-positive patients (131/208) and lowest in the ER + PR + HER2-positive patients (19/73). The subgroup analyses showed that there was no significant difference in pCR rate among the neoadjuvant chemotherapy regimens in ER positive, PR positive, HER2 IHC 2 + , Ki67 index < 30% population. However, for ER-PR-HER2-positive patients, the neoadjuvant chemotherapy regimen has a great influence on the pCR rates. CONCLUSIONS: Patients with ER-negative, PR-negative, HER2 3 + and high KI-67 index were more likely to achieve pCR. THP may be used as an alternative to AC-THP or TCbHP in selected HER2-positive patients.

Survival outcomes in HER2-low versus HER2-zero breast cancer after neoadjuvant chemotherapy: a meta-analysis.

BACKGROUND: The survival outcomes in HER2-low versus HER2-zero breast cancer (BC) after neoadjuvant chemotherapy (NACT) remain unclear. The meta-analysis was conducted to summarize current evidence about the survival outcomes in HER2-low versus HER2-zero BC. METHODS: We conducted a systematic search in PubMed and EMBASE databases to identify relevant studies. RESULTS: A total of 14 studies with 53,714 patients were included. Overall, 34,037 patients (63.37%) were HER2-low, and 19,677 patients (36.63%) were HER2-zero. Patients with HER2-low tumors had a significantly lower pathological complete response (pCR) rate than patients with HER2-zero tumors, regardless of the hormone receptor status. Compared with HER2-zero breast cancer, the overall survival (OS) and disease-free survival (DFS) of HER2-low BC were longer in the overall cohort (HR = 0.72; 95% CI = 0.61-0.85; P < 0.0001; HR = 0.83; 95% CI = 0.75-0.92; P = 0.0002); however, no differences were observed in terms of OS and DFS between HER2-low and HER2-zero BC in the HR-negative group. In the HR-positive group, HER2-low status had no significant impact on OS, while significantly associated with increased DFS (HR = 0.85; 95% CI = 0.76-0.96; P = 0.007). CONCLUSION: These results suggest that although HER2-low BC has a poor response to NACT, it is correlated with favorable OS and DFS after NACT in the overall cohort as well as longer DFS in the HR-positive group.

CMTM7 inhibits breast cancer progression by regulating Wnt/ß-catenin signaling.

BACKGROUND: Breast cancer is the major cause of death in females globally. Chemokine-like factor like MARVEL transmembrane domain containing 7 (CMTM7) is reported as a tumor suppressor and is involved in epidermal growth factor receptor degradation and PI3K/AKT signaling in previous studies. However, other molecular mechanisms of CMTM7 remain unclear. METHODS: The expression level of CMTM7 in breast cancer cells and tissues was detected by qRT-PCR and western blot, and the methylation of CMTM7 promoter was detected by BSP sequencing. The effect of CMTM7 was verified both in vitro and in vivo, including MTT, colony formation, EdU assay, transwell assay and wound healing assay. The interaction between CMTM7 and CTNNA1 was investigated by co-IP assay. The regulation of miR-182-5p on CMTM7 and TCF3 on miR-182-5p was detected by luciferase reporter assay and ChIP analysis. RESULTS: This study detected the hypermethylation levels of the CMTM7 promoter region in breast cancer tissues and cell lines. CMTM7 was performed as a tumor suppressor both in vitro and in vivo. Furthermore, CMTM7 was a direct miR-182-5p target. Besides, we found that CMTM7 could interact with Catenin Alpha 1 (CTNNA1) and regulate Wnt/ß-catenin signaling. Finally, transcription factor 3 (TCF3) can regulate miR-182-5p. We identified a feedback loop with the composition of miR-182-5p, CMTM7, CTNNA1, CTNNB1 (ß-catenin), and TCF3, which play essential roles in breast cancer progression. CONCLUSION: These findings reveal the emerging character of CMTM7 in Wnt/ß-catenin signaling and bring new sights of gene interaction. CMTM7 and other elements in the feedback loop may serve as emerging targets for breast cancer therapy.

PAX5-miR-142 feedback loop promotes breast cancer proliferation by regulating DNMT1 and ZEB1.

BACKGROUND: Breast cancer is one of the most common malignancies occurred in female around the globe. Recent studies have revealed the crucial characters of miRNA and genes, as well as the essential roles of epigenetic regulation in breast cancer initiation and progression. In our previous study, miR-142-3p was identified as a tumor suppressor and led to G2/M arrest through targeting CDC25C. However, the specific mechanism is still uncertain. METHODS: We identified PAX5 as the upstream regulator of miR-142-5p/3p through ALGGEN website and verified by series of assays in vitro and in vivo. The expression of PAX5 in breast cancer was detected by qRT-PCR and western blot. Besides, bioinformatics analysis and BSP sequencing were performed to analyze the methylation of PAX5 promoter region. Finally, the binding sites of miR-142 on DNMT1 and ZEB1 were predicted by JASPAR, and proved by luciferase reporter assay, ChIP analysis and co-IP. RESULTS: PAX5 functioned as a tumor suppressor by positive regulation of miR-142-5p/3p both in vitro and in vivo. The expression of PAX5 was regulated by the methylation of its promoter region induced by DNMT1 and ZEB1. In addition, miR-142-5p/3p could regulate the expression of DNMT1 and ZEB1 through binding with their 3'UTR region, respectively. CONCLUSION: In summary, PAX5-miR-142-DNMT1/ZEB1 constructed a negative feedback loop to regulate the progression of breast cancer, which provided emerging strategies for breast cancer therapy.

Clinicopathological characteristics, local treatment, and prognostic factors in IE/IIE primary breast lymphoma: a retrospective study of 67 patients.

INTRODUCTION: Primary breast lymphoma (PBL) is a rare disease, treatment of which excerpts does not reach a consensus. This retrospective study was conducted to analyze clinical features and survival outcomes of different therapeutic methods. MATERIALS AND METHODS: Records of 67 patients with stage IE/IIE primary breast lymphoma were reviewed from the medical record system. Survival information was gathered by searching the outpatient system. Clinicopathological characteristics were compared by chi-squared or Fisher's exact tests. A comparison of survival curves was performed by log-rank tests. The Cox proportional hazard model was applied for multivariate analysis. RESULTS: At the median follow-up time of 65.23 months (range, 9-150 months), there were 27 (40.3%) relapses, 28 (41.8%) distant metastases, and 21 (31.3%) deaths. The 5-year progression-free survival (PFS) and overall survival (OS) were 52.1% and 72.4%. Pathological types (DLBCL vs. non-DLBCL, p = 0.001) and rituximab use (p < 0.001) were statistically associated with longer PFS in patients with PBL. Nodal sites involved and radiotherapy administration were significant predictors for 5-year OS. Multivariate analysis suggested that nodal sites involved (p = 0.005) and radiotherapy administration (p < 0.003) were independent prognostic factors for OS in patients with PBL (p < 0.05). Radical surgery was not an independent factor for patients with PBL. CONCLUSIONS: Radiotherapy improved the survival of patients with PBL. Radical mastectomy offered no additional benefit in the treatment of PBL.

Immediate surgical mesh-free implant-based breast reconstruction with fascial flap in breast cancer patients after mastectomy.

PURPOSE: Surgical meshes are often used in retro-pectoral implant-based breast reconstruction (IBBR) to improve lower pole expansion. However, using of surgical meshes is associated with increased complications and costs. To solve this problem, we have adopted a modified fascia-based IBBR technique using fasciae of pectoral major, serratus anterior, and external oblique muscles to form a sling covering the lower pole of prosthesis since 2014. METHODS: Data of 788 retro-pectoral IBBR cases, including 250 fascia-based IBBR cases (fascial group) and 538 traditional IBBR cases (control group), treated between 2014 and 2019 were retrospectively analyzed. The surgical outcomes of the fascial and control group were compared. The primary endpoint was the rate of post-operative complications requiring interventions. The secondary endpoint was the rate of explantation. The exploratory endpoint was the time from surgery to complication and explantation. RESULTS: The fascial group had significantly lower rates of developing major post-operative complications (1.2 vs. 6.1%, p = 0.002) and losing prostheses (1.2 vs. 4.3%, p = 0.025), as compared with the control group. The median time from surgery to complication and explantation were 61 (range, 35-115) days and 92 (range, 77-134) days for the fascial group and 35 (range, 6-239) days and 63 (range, 23-483) days for the control group, respectively. CONCLUSION: Fascia-based IBBR technique had low rates of major post-operative complications and explantation. Fascia-based IBBR technique could be considered as an alternative reconstruction method in properly selected patients.

ZNF384-ZEB1 feedback loop regulates breast cancer metastasis.

BACKGROUND: Breast cancer has become the most frequently diagnosed cancer worldwide. Increasing evidence indicated that zinc finger proteins (ZNFs), the largest family of transcription factors, contribute to cancer development and progression. Although ZNF384 is overexpressed in several types of human cancer, the role of ZNF384 in breast cancer remains unknown. Therefore, our research focused on ZNF384 regulation of the malignant phenotype of breast cancer and the underlying molecular mechanisms. METHODS: CCK-8 and colony formation assays were used to evaluate cell proliferation. Transwell and scratch assays were used to evaluate the cell migration and invasion. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were used to confirm the target relationship between ZNF384 and zinc finger E-box binding homeobox 1 (ZEB1). Xenografts were used to monitor the targets in vivo effects. RESULTS: We noted that ZNF384 was significantly overexpressed in breast cancer and highlighted the oncogenic mechanism of ZNF384. ZNF384 transactivated ZEB1 expression and induced an epithelial and mesenchymal-like phenotype, resulting in breast cancer metastasis. Furthermore, ZNF384 may be a target of miR-485-5p, and ZEB1 can up-regulate ZNF384 expression by repressing miR-485-5p expression. Together, we unveiled a feedback loop of ZNF384-ZEB1 in breast cancer metastasis. CONCLUSIONS: The findings suggest that ZNF384 can serve as a prognostic factor and a therapeutic target for breast cancer patients.

The functions and prognostic value of Krüppel-like factors in breast cancer.

BACKGROUND: Krüppel-like factors (KLFs) are zinc finger proteins which participate in transcriptional gene regulation. Although increasing evidence indicate that KLFs are involved in carcinogenesis and progression, its clinical significance and biological function in breast cancer are still limited. METHODS: We investigated all the expression of KLFs (KLF1-18) at transcriptional levels by using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). The mRNA and protein expression levels of KLFs were also determined by using RT-qPCR and immunohistochemistry, respectively. CBioPortal, GeneMANIA and STRING were used to comprehensive analysis of the molecular characteristics of KLFs. The clinical value of prognostic prediction based on the expression of KLFs was determined by using the KM plotter. The relevant molecular pathways of KLFs were further analyzed by using Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Finally, we investigated the effect of KLF2 and KLF15 on biological behavior of breast cancer cells in vitro. RESULTS: The expression of KLF2/4/6/8/9/11/15 was significantly down-regulated in breast cancer. The patients with high KLF2, KLF4 or KLF15 expression had a better outcome, while patients with high KLF8 or KLF11 had a poor prognosis. Furthermore, our results showed that KLF2 or KLF15 can be used as a prognostic factor independent on the other KLFs in patients with breast cancer. Overexpression of KLF2 or KLF15 inhibited cell proliferation and migration, and blocked cell cycle at G0/G1 phase, resulting in cell apoptosis. CONCLUSIONS: KLF2 and KLF15 function as tumor suppressors in breast cancer and are potential biomarkers for prognostic prediction in patients with breast cancer.

An Improved Nomogram to Reduce False-Positive Biopsy Rates of Breast Imaging Reporting and Data System Ultrasonography Category 4A Lesions.

BACKGROUND: The NCCN clinical guidelines recommended core needle biopsy for breast lesions classified as Breast Imaging Reporting and Data System (BI-RADS) 4, while category 4A lesions are only 2-10% likely to be malignant. Thus, a large number of biopsies of BI-RADS 4A lesions were ultimately determined to be benign, and those unnecessary biopsies may incur additional costs and pains. However, it is important to emphasize that the current risk prediction model focuses primarily on the details and complex risk features of US or MG findings, which may be difficult to apply in order to benefit from the model. To stratify and manage BI-RADS 4A lesions effectively and efficiently, a more effective and practical predictive model must be developed. METHODS: We retrospectively analyzed 465 patients with BI-RADS ultrasonography (US) category 4A lesions, diagnosed between January 2019 and July 2019 in Tianjin Medical University Cancer Institute and Hospital and National Clinical Research Center for Cancer. Univariate and multivariate logistic regression analyses were conducted to identify risk factors. To stratify and predict the malignancy of BI-RADS 4A lesions, a nomogram combining the risk factors was constructed based on the multivariate logistic regression results. In order to determine the predictive performance of our predictive model, we used the concordance index (C-index), calibration curve, and receiver operating characteristic (ROC), and the decision curve analysis (DCA) to assess the clinical benefits. RESULTS: Based on our analysis, 16.3% (76 out of 465) of patients were pathologically diagnosed with malignant lesions, while 83.6% (389 out of 465) were diagnosed with benign lesions. According to univariate and multivariate logistic regression analysis, age (OR = 3.414, 95%CI:1.849-6.303), nipple discharge (OR = .326, 95%CI:0.157-.835), palpable lesions (OR = 1.907, 95%CI:1.004-3.621), uncircumscribed margin (US) (OR = 1.732, 95%CI:1.033-2.905), calcification (mammography, MG) (OR = 2.384, 95%CI:1.366-4.161), BI-RADS(MG) (OR = 5.345, 95%CI:2.934-9.736) were incorporated into the predictive nomogram (C-index = .773). There was good agreement between the predicted risk and the observed probability of recurrence. Furthermore, we determined that 153 was the best cutoff score for distinguishing between patients in the low- and high-risk groups. Malignant lesions were significantly more prevalent in high-risk patients than in low-risk patients. CONCLUSION: Based on clinical, US, and MG features, we present a predictive nomogram to reliably predict the malignancy risk of BI-RADS(US) 4A lesions, which may assist clinicians in the selection of patients at low risk of malignancy and reduce the number of false-positive biopsies.

Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case-control study in Chinese population.

BACKGROUND: Perfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population. METHODS: Participants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer. RESULTS: Perfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (ORER+ = 1.47, 95% CI: 1.19, 1.80; ORPR+ = 1.36, 95% CI: 1.09, 1.69; ORHER2 = 1.62, 95% CI: 1.19, 2.21). CONCLUSIONS: Overall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal.

The functions and prognostic values of m6A RNA methylation regulators in thyroid carcinoma.

BACKGROUND: N6-Methyladenosine (m6A) is the most common RNA modification and regulates RNA splicing, translation, translocation, and stability. Aberrant expression of m6A has been reported in various types of human cancers. m6A RNA modification is dynamically and reversibly mediated by different regulators, including methyltransferase, demethylases, and m6A binding proteins. However, the role of m6A RNA methylation regulators in thyroid cancer remains unknown. The aim of this study is to investigate the effect of the 13 main m6A RNA modification regulators in thyroid carcinoma. METHODS: We obtained clinical data and RNA sequencing data of 13 m6A RNA methylation regulators from The Cancer Genome Atlas (TCGA) THCA database. We performed consensus clustering to identify the clinical relevance of m6A RNA methylation regulators in thyroid carcinoma. Then we used LASSO Cox regression analysis to generate a prognostic signature based on m6A RNA modification regulator expression. Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Gene Set Enrichment Analyses were performed to explore differential cellular processes and signaling pathways between the two groups based on risk signature. RESULTS: We found that most of the m6A RNA modification regulators are down-regulated in 450 patients with thyroid carcinoma. We derived a three m6A RNA modification regulator genes-based risk signature (FTO, RBM15 and KIAA1429), that is an independent prognostic biomarker in patients with thyroid carcinoma. Moreover, we found that this risk signature could better predict outcome in male than female. Functional research in vitro demonstrated that the m6A RNA methylation regulators involved in the model acted significant role in the proliferation and migration of thyroid cancer cells. CONCLUSIONS: Our study revealed the influence of m6A RNA methylation regulators on thyroid carcinoma through biological experiments and three-gene prognostic model.

Current Status and Factors Influencing Surgical Options for Breast Cancer in China: A Nationwide Cross-Sectional Survey of 110 Hospitals.

BACKGROUND: There are limited nationwide data regarding breast cancer surgery in China. The Chinese Anti-Cancer Association's Committee of Breast Cancer Society and the Chinese Society of Breast Surgeons conducted a nationwide survey to examine the use of and barriers associated with surgical options among patients with breast cancer. METHODS: Surveys were sent via e-mail to the directors of 110 centers that performed at least 200 breast cancer operations in 2017. The electronic questionnaire contained 183 questions and covered six aspects, including demographic information about the hospitals and surgeons, surgical practice, and application of breast reconstruction. RESULTS: The selected hospitals were from 31 provinces or municipalities. The overall proportion of breast-conserving surgery (BCS) was 22%. Local gross domestic product was significantly related to the rate of BCS (p = .046). Sentinel lymph node biopsy was performed routinely in 76% of hospitals. Only 14.5% (16/110) of hospitals used the dual-tracer method, including radioisotopes. For patients with cN0 disease receiving BCS with one or two positive sentinel lymph nodes, 20% (22/110) of hospitals accepted omitting axillary lymph node dissection (ALND). For patients who underwent mastectomy, only 4% (4/110) of hospitals accepted omitting ALND. There was an obvious polarization trend in the proportion of oncoplastic breast-conserving surgery (OPS); 35/110 (32%) performed OPS in fewer than 10% of cases, whereas 36/110 (33%) performed OPS in more than 50% of cases. OPS was more likely to be performed in academic hospitals. Volume displacement was more commonly used than volume replacement (p < .001). Breast reconstruction was routinely performed in 96/110 (87%) of hospitals, 62% of which involved cooperation with the plastic surgery department. Factors influencing breast reconstruction after mastectomy included the establishment of a plastic surgery department, regional economy, and cooperation between the plastic and general surgery departments. Overall, the proportion of breast reconstruction procedures after mastectomy was 10.7%, with 70% being implant-based reconstruction, 17% autologous tissue reconstruction, and 13% a combination. Overall, 22% of the hospitals predominantly performed immediate breast reconstruction. For delayed reconstruction, two-stage implant-based breast reconstruction was the first choice for 46% of centers, whereas 20% of centers chose autologous reconstruction. Among the 96 centers that performed autologous-based reconstruction, 96% performed latissimus dorsi flap reconstruction, 65% performed transverse rectus abdominis musculocutaneous flap reconstruction, and 45% used deep inferior epigastric artery perforator flaps. CONCLUSION: The results are of great value for promoting the implementation of a consensus on diagnostic and treatment standards, development of guidelines for breast cancer, and training of breast specialists. IMPLICATIONS FOR PRACTICE: This study aimed to establish comprehensive baseline data on the status of current breast cancer treatment in China by presenting the statistics on clinical treatments and surgeries, the distribution of clinical stages, and the demographic characteristics of patients. This report is based on a survey conducted by the Chinese Anti-Cancer Association's Committee of Breast Cancer Society and the Chinese Society of Breast Surgeons, which examined the use of breast cancer surgical options in hospitals all over the country and the factors hindering the adoption of procedures and techniques. This study makes a significant contribution to the literature because there are limited nationwide data regarding breast cancer surgery in China.

Downregulation of microRNA-1469 promotes the development of breast cancer via targeting HOXA1 and activating PTEN/PI3K/AKT and Wnt/ß-catenin pathways.

Breast cancer (BC) is a common malignancy which is the most frequently diagnosed cancer in women all over the worldwide. This study aimed to investigate the roles of miR-1469 in the development of BC, as well as its regulatory mechanism. The expression levels of miR-1469 in BC tissues, serum, and cell lines were determined. Effects of overexpression of miR-1469 on MCF7 cell viability, colony-forming ability, apoptosis, migration, and invasion were then investigated. Furthermore, the potential target of miR-1469 in MCF7 cells was explored. Besides, the association between miR-1469, PTEN/PI3K/AKT, and Wnt/ß-catenin pathways was elucidated. Notably, confirmatory experiments by downregulation of miR-1469 in SK-BR-3 cells were further performed. The miR-1469 expression was significantly downregulated in BC tissues, serum, and cell lines. The overexpression of miR-1469 significantly inhibited the proliferation, arrested cell-cycle at G2/M phase, increased apoptosis, suppressed migration, and invasion of MCF-7 cells. In addition, HOXA1 was verified as a direct target of miR-1469, and the effects of overexpression of miR-1469 on the malignant behaviors of MCF7 cells were significantly counteracted by overexpression of HOXA1 concurrently. Furthermore, the overexpression of miR-1469 suppressed the activation of PTEN/PI3K/AKT and Wnt/ß-catenin pathways, which was reversed overexpression of HOXA1 concurrently. Besides, confirmatory experiments showed that the inhibition of miR-1469 promoted the malignant behaviors of SK-BR-3 cells, which was inversed after miR-1469 inhibition and HOXA1 knockdown at the same time. Our findings reveal that downregulation of miR-1469 may promote the development of BC by targeting HOXA1 and activating PTEN/PI3K/AKT and Wnt/ß-catenin pathways. MiR-1469 may serve as a promising target for BC therapy.

Association of PTPN1 polymorphisms with breast cancer risk: A case-control study in Chinese females.

BACKGROUND: Breast cancer (BC) risk, development, and prognosis were closely related to obesity, diabetes mellitus, and metabolic syndrome. Protein tyrosine phosphatase, non-receptor type 1 (PTPN1) located on chromosome 20q13, could negatively regulate insulin and leptin signaling. In this study, we determined the association of PTPN1 polymorphisms with BC risk. METHODS: We analyzed the distribution of 11 selected PTPN1 single nucleotide polymorphisms in Chinese female patients with BC (n = 953) and healthy controls (n = 963) based on a multicenter case-control study. The association of PTPN1 genotypes and haplotypes frequencies with BC risk were determined by logistic regression analysis. Analyses were further stratified by body mass index (BMI), waist-hip rate (WHR), diabetes mellitus history, and fasting plasma glucose level. The eQTL (expression Quantitative Trait Loci) analysis for PTPN1 was conducted by GTEx database. RESULTS: There were significant differences between BC cases and control groups in menopausal status, number of births, and BMI. Four single nucleotide polymorphisms (SNPs; rs3215684, rs3787345, rs718049, and rs718050) decreased overall BC risk, and other seven SNPs showed no significant association with BC risk. In multivariate analysis, BMI and rs3215684 DT + DD genotype were identified as independent risk factors for BC, and mutated genotypes of rs3215684 were correlated with increased PTPN1 expression. There are no haplotypes showed different frequencies between cases and controls. In the stratified analysis, rs2206656 showed a significant association with decreased BC risk in the subgroup of BMI ≤ 24 kg/m 2 , while rs3215684 and rs718049 showed lower BC risk in the subgroup of WHR > 0.85. Seven SNPs showed lower BC risk in the subgroup with diabetes mellitus history and/or fasting plasma glucose level ≥ 7 mM, while rs754118 decreased BC risk in the subgroup of fasting plasma glucose level < 7 mM. CONCLUSION: Our findings suggest that PTPN1 SNPs associated with BC susceptibility in Chinese females, which also suggested a novel mechanism between obesity, diabetes mellitus, and BC risk.

KRT19 and CEACAM5 mRNA-marked circulated tumor cells indicate unfavorable prognosis of breast cancer patients.

AIM: To investigate the clinical and prognostic significance of circulated tumor cells (CTC) marked by cytokeratin 19 coding gene KRT19 mRNA and carcinoembryonic antigen coding gene CEACAM5 mRNA in preoperative peripheral blood of breast cancer patients and provide molecular markers for breast cancer metastasis risk. METHODS: The mRNA levels of KRT19 and CEACAM5 in preoperative peripheral blood of breast cancer patients without (n = 603) and with (n = 76) distant metastases at the time of initial diagnosis were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The relationship between CTCKRT19, CTCCEACAM5 and clinicopathological features, local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), or overall survival (OS) was statistically analyzed. RESULTS: In different pathological stages of breast cancer, the rates of CTCKRT19-pos and CTCCEACAM5-pos increased with the increase of the stages (P = 0.077 and P = 0.004). Preoperative CTCKRT19-pos in breast cancer patients was closely related to the lymph node metastasis statues (P < 0.0001), and had no significant correlation with other clinicopathological features. There was no significant correlation between CTCCEACAM5 and the clinicopathological features. Patients with high levels of CTC double-marked by KRT19 and CEACAM5 mRNA had shorter DMFS (P < 0.0001) and OS (P = 0.016) for patients with breast cancer. The 7-year DMFS rates for the low-, intermediate-, and high-risk groups were 90.7%, 67.5%, and 59.1%, respectively (P < 0.0001). The prognosis of patients with decreased KRT19 and CEACAM5 mRNA after treatment is better than that of patients who have not decreased, and the combination of the two indicators is better than the single one for predicting PFS (P = 0.002 compare with P = 0.036 or P = 0.047). CONCLUSION: Double-marked CTC by KRT19 and CEACAM5 mRNA is a prognostic index of breast cancer patients before surgery and after chemotherapy. Single-marked CTC by KRT19 mRNA indicates lymph node statues of preoperative patients. Therefore, the RT-qPCR-based molecular diagnosis of CTC could be used for prognostic prediction of breast cancer patients and guiding clinical treatment.

miR-190-5p in human diseases.

miRNAs, a major class of small noncoding RNAs approximately 18-25 nucleotides in length, function by repressing the expression of target genes through binding to complementary sequences in the 3'-UTRs of target genes. Emerging evidence has highlighted their important roles in numerous diseases, including human cancers. Recently, miR-190 has been shown to be dysregulated in various types of human cancers that participates in cancer-related biological processes, including proliferation, apoptosis, metastasis, drug resistance, by regulating associated target genes, and to predict cancer diagnosis and prognosis. In this review, we summarized the roles of miR-190-5p in human diseases, especially in human cancers. Then we classified its target genes in tumorigenesis and progression, which might provide evidence for cancer diagnosis and prognosis, promising tools for cancer treatment, or leads for further investigation.

miR-190 suppresses breast cancer metastasis by regulation of TGF-ß-induced epithelial-mesenchymal transition.

BACKGROUND: Breast cancer is the most common cancer among women worldwide and metastasis is the leading cause of death among patients with breast cancer. The transforming growth factor-ß (TGF-ß) pathway plays critical roles during breast cancer epithelial-mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-ß signaling, promotes breast cancer metastasis through induction of EMT. METHODS: The expression of miR-190 and SMAD2 in breast cancer tissues, adjacent normal breast tissues and cell lines were determined by RT-qPCR. The protein expression levels and localization were analyzed by western blotting and immunofluorescence. ChIP and dual-luciferase report assays were used to validate the regulation of ZEB1-miR-190-SMAD2 axis. The effect of miR-190 on breast cancer progression was investigated both in vitro and in vivo. RESULTS: miR-190 down-regulation is required for TGF-ß-induced EMT. miR-190 suppresses breast cancer metastasis both in vitro and in vivo by targeting SMAD2. miR-190 expression is down-regulated and inversely correlates with SMAD2 in breast cancer samples, and its expression level was associated with outcome in patients with breast cancer. Furthermore, miR-190 is transcriptionally regulated by ZEB1. CONCLUSIONS: Our data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-ß network in breast cancer metastasis.

miR-485-5p suppresses breast cancer progression and chemosensitivity by targeting survivin.

Breast cancer is the most common cancer among women worldwide. Chemoresistance remains to be a considerable obstacle in breast cancer therapy and it is often involves dysregulation of a variety of microRNAs (miRNAs). miR-485-5p functions as a tumor suppressor in several types of human cancers. However, its role in breast cancer chemosensitivity have not been determined. In the present study, we demonstrated that overexpression of miR-485-5p suppresses breast cancer progression and enhances chemosensitivity both in vitro and in vivo. Further study demonstrated that miR-485-5p directly targeted the 3'-untranslated region of survivin and overexpression of survivin overcomes the miR-485-5p induced effects on breast cancer. In conclusion, our study identified that miR-485-5p suppresses cancer progression and enhances the chemosensitivity by targeting survivin. Targeting survivin by miR-485-5p may provide a potential approach to reverse chemosensitivity in breast cancer cells.

Downregulation of delta-aminolevulinate dehydratase is associated with poor prognosis in patients with breast cancer.

Delta-aminolevulinate dehydratase (ALAD) catalyzes the second step in the biosynthesis of heme and is also an endogenous inhibitor of the 26S proteasome. The role of ALAD in breast cancer progression is still unclear. In this study, we found that the expression of ALAD was downregulated in breast cancer tissues compared with adjacent normal breast tissues. Enhanced ALAD expression was associated with a favorable outcome in patients with breast cancer. Overexpression of ALAD suppresses breast cancer cell proliferation and invasion and inhibits the epithelial-mesenchymal transition phenotype. Furthermore, we found that ALAD regulates transforming growth factor-ß-mediated breast cancer progression. This finding suggests that ALAD might be a potential biomarker for breast cancer that suppresses breast cancer progression by regulating transforming growth factor-ß-mediated epithelial-mesenchymal transition.