Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart.

While the heart regenerates poorly in mammals, efficient heart regeneration occurs in zebrafish. Studies in zebrafish have resulted in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. To identify which processes occur in proliferating cardiomyocytes we have used a single-cell RNA-sequencing approach. We uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the nonproliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Furthermore, we find that the metabolic reprogramming of border zone cardiomyocytes is induced by Nrg1/ErbB2 signaling and is important for their proliferation. This mechanism is conserved in murine hearts in which cardiomyocyte proliferation is induced by activating ErbB2 signaling. Together these results demonstrate that glycolysis regulates cardiomyocyte proliferation during heart regeneration.

High peroxidasin-like expression is a potential and independent prognostic biomarker in breast cancer.

Breast cancer is a frequent female malignant tumor with high mortality and poor prognosis. Peroxidasin like (PXDNL) has many biological functions, including characteristic activity of hormone biosynthesis, host defense, and cell motility. In addition, PXDNL is closely connected with the progression of breast cancer. In this study, we found that PXDNL may be an independent prognostic biomarker of breast cancer.We tested the mRNA expression of PXDNL in breast cancer by detecting The Cancer Genome Atlas (TCGA) database. The chi-squared test was used to evaluate clinical correlation. The receiver operating characteristic (ROC) curves were drawn to evaluate diagnosis potential in breast cancer. Subsequently, survival analyses were performed to identify the relevance between the expression of PXDNL and the overall survival/relapse-free survival of patients with breast cancer. Univariate/multivariate Cox regression model was executed to detect risk factors affecting the prognosis of patients with breast cancer.PXDNL is highly expressed in breast cancer tissues and is related to survival status of patients. The ROC curve showed that PXDNL had beneficial diagnostic ability in breast cancer. Survival analysis indicated that patients with breast cancer with high PXDNL expression generally had decreased overall survival/relapse-free survival. Univariate/multivariate Cox model analyses further suggested an association between PXDNL expression and prognosis of patients with breast cancer.High PXDNL expression is a potential and independent prognostic biomarker in breast cancer.

Dasatinib inhibition of cSRC prevents the migration and metastasis of canine mammary cancer cells with enhanced Wnt and HER signalling.

Human epidermal growth factor 2 (HER2) overexpression leads to aggressive mammary tumour growth. Although the prognosis of HER2+ tumours in humans is greatly improved using biologicals, therapy resistance, which may be caused by increased phosphatidyl-3-kinase (PI3K), rous sarcoma proto-oncogene (cSRC) or wingless-type MMTV integration site family (Wnt) activity, is a major concern. A recent analysis of 12 canine mammary cell lines showed an association between HER2/3 overexpression and phosphatase and tensin homologue (PTEN) deletion with elevated Wnt-signalling. Wnt-activity appeared to be insensitive to phosphatidyl-3-kinase (PI3K) inhibitors but sensitive to Src-I1. We hypothesized that Wnt activation, was caused by HER2/3-activated cSRC activation. The role of HER2/3 on Wnt signalling was investigated by silencing HER2/3 expression using specific small interfering RNA (siRNAs). Next, the effect of an epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor on Wnt activity and migration was investigated and compared to other tyrosine kinase inhibitors (TKIs) of related signalling pathways. Finally, two TKIs, a cSRC and a PI3K inhibitor, were investigated in a zebrafish xenograft model. Silencing of HER1-3 did not inhibit the intrinsic high Wnt activity, whereas the HER kinase inhibitor afatinib showed enhanced Wnt activity. The strongest inhibition of Wnt activity and cell viability and migration was shown by cSRC inhibitors, which also showed strong inhibition of cell viability and metastasis in a zebrafish xenograft model. HER2/3 overexpression or HER2/3-induced cSRC activation is not the cause of enhanced Wnt activity. However, inhibition of cSRC resulted in a strong inhibition of Wnt activity and cell migration and metastasis. Further studies are needed to unravel the mechanism of cSRC activation and cSRC inhibition to restore sensitivity to HER-inhibitors in HER2/3-positive breast cancer.

Nucleostemin expression in breast cancer is a marker of more aggressive phenotype and unfavorable patients' outcome: A STROBE-compliant article.

Cancer stem cells (CSCs) are postulated to play significant role in the pathogenesis, progression as well as drug resistance of breast cancer. Nucleostemin (NS) is thought to be a key molecule for stemness, and the clinical impact of NS immunoreactivity in breast cancer can indicate its actual role and future therapeutic potentials.The current study is an observational study with an attempt to evaluate the correlation between NS expression (protein and gene expression levels) and different clinicopathological attributes of invasive breast cancer. For that reason, we investigated NS immunohistochemistry expression on commercial tissue microarray (TMA) of 102 patients and 51 archival specimens from patients admitted to Saqr Hospital, Ras Al Khaimah and diagnosed in Al Baraha Hospital, Dubai, UAE. In addition, the association between NS (GNL3) gene expression and different prognostic parameters as well as patient outcome was also evaluated using 2 large publicly available databases.Interestingly, we found NS expression to be associated with less differentiated and more advance stage. In addition, NS expression was significantly higher in larger size (P = .001) and LN-positive tumors (P = .007). Notably, NS expression was significantly correlated to P53 positive (P = .037) status. Furthermore, NS was found to be more expressed in the highly aggressive breast cancer subtypes including human epidermal growth factor receptor 2 (HER-2) and triple negative breast cancer (TNBC) subtypes. Moreover, our results also showed that high GNL3 gene expression to be associated with poor patient outcome and higher chances of tumor recurrence.Our results highlight NS expression as a marker of aggressive phenotype and poor outcome and indicate its possible use as a potential target for CSC-associated breast cancer management.

Prognositic significance of P-cadherin expression in breast cancer: Protocol for a meta-analysis.

BACKGROUND: P-cadherin is a calcium-dependent cell-cell adhesion glycoprotein. It has been implicated in invasiveness and metastasis. However, the clinical prognostic value of overexpression of P-cadherin in patients with breast cancer (BC) remains unsettled. METHODS: A systematic literature search will be performed in all available databases to quantitatively review eligible studies and identify all relevant data, which could be used to detect the relationship between overexpression of P-cadherin and overall survival (OS), disease-free survival (DFS), and clinicopathological parameters. Hazard ratio and 95% confidence intervals (CIs) or P value will be employed as effect measures to estimate the correlation between P-cadherin and the oncologic outcomes including overall survival (OS), disease-free survival (DFS). Odds ratios (ORs) and the 95% CIs will be evaluated for the pooled analysis of the correlation between P-cadherin expression and clinicopathological features. We will use the Review Manager (Revman) 5.3.5 software (Cochrane Community, London, United Kingdom) and STATA 14 software (version 14.0; Stata Corp, College Station, TX) to perform the meta-analysis to calculate the data. RESULTS: The review will provide a high-quality synthesis of current evidence of the prognostic role of P-cadherin in BCs. The results will be published in a peer-reviewed journal. CONCLUSION: We hope that the results of this study will provide significant evidence to assess whether the expression of P-cadherin is associated with poor prognosis in patients with BC. PROSPERO REGISTRATION NUMBER: This meta-analysis protocol has been registered in the PROSPERO network with registration number: CRD42019119880.

The Effects of Silencing the Her2 Gene on Proliferation and Angiogenesis of Meningioma Cells in vivo and in vitro.

Despite the molecular mechanisms of meningioma having been elucidated, the curative effects of current treatments for invasive and malignant meningiomas have been unsatisfactory. Our previous study found that HER2 protein was overexpressed in human meningiomas. However, only a few studies regarding the correlation between meningiomas and HER2 have been reported. The present study aimed to investigate the influence of silencing the Her2 gene on the proliferation and angiogenesis of human malignant meningioma cells. Human malignant meningioma cells were transfected successfully by special shRNA. After lentivirus infection, mRNA and protein levels of Her2 in the shRNA group were significantly reduced. Cell viability began to decrease at 72 h and was most strongly inhibited at 96 h, as measured by CCK-8 assay. Protein levels of Ki-67 and VEGF in the Her2-sh group were significantly lower than in the control and mock groups. After injecting tumor cells into nude mice, the tumor volume was significantly lower in the Her2-sh group, and protein levels of Ki-67, VEGF and CD34 were significantly lower in Her2-sh group than in the control and mock groups. The results demonstrated that silencing Her2 may inhibit the proliferation and angiogenesis of human meningioma cells.

Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation.

Hemodynamic shear force has been implicated as modulating Notch signaling-mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf. Genetic manipulations were performed to reduce hematopoiesis and inhibit atrial contraction to lower WSS in synchrony with attenuation of oscillatory shear index (OSI) during ventricular development. γ-Secretase inhibitor of Notch intracellular domain (NICD) abrogated endocardial and epicardial Notch activity. Rescue with NICD mRNA restored Notch activity sequentially from the endocardium to trabecular grooves, which was corroborated by observed Notch-mediated cardiomyocyte proliferations on WT zebrafish trabeculae. We also demonstrated in vitro that a high OSI value correlated with upregulated endothelial Notch-related mRNA expression. In silico computation of energy dissipation further supports the role of trabeculation to preserve ventricular structure and contractile function. Thus, spatiotemporal variations in WSS coordinate trabecular organization for ventricular contractile function.

Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-ß1 (NRG1ß), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells.

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. METHODS: We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. RESULTS: Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. LIMITATIONS: Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. CONCLUSIONS: Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver-Dependent Manner.

Using a novel mouse model, a mitochondrial-nuclear exchange model termed MNX, we tested the hypothesis that inherited mitochondrial haplotypes alter primary tumor latency and metastatic efficiency. Male FVB/N-Tg(MMTVneu)202Mul/J (Her2) transgenic mice were bred to female MNX mice having FVB/NJ nuclear DNA with either FVB/NJ, C57BL/6J, or BALB/cJ mtDNA. Pups receiving the C57BL/6J or BALB/cJ mitochondrial genome (i.e., females crossed with Her2 males) showed significantly (P < 0.001) longer tumor latency (262 vs. 293 vs. 225 days), fewer pulmonary metastases (5 vs. 7 vs. 15), and differences in size of lung metastases (1.2 vs. 1.4 vs. 1.0 mm diameter) compared with FVB/NJ mtDNA. Although polyoma virus middle T-driven tumors showed altered primary and metastatic profiles in previous studies, depending upon nuclear and mtDNA haplotype, the magnitude and direction of changes were not the same in the HER2-driven mammary carcinomas. Collectively, these results establish mitochondrial polymorphisms as quantitative trait loci in mammary carcinogenesis, and they implicate distinct interactions between tumor drivers and mitochondria as critical modifiers of tumorigenicity and metastasis. Cancer Res; 77(24); 6941-9. ©2017 AACR.

HER2 overexpression is associated with worse outcomes in patients with upper tract urothelial carcinoma (UTUC).

PURPOSE: The aim of our study was to evaluate the expression pattern of HER2 overexpression in patients with upper tract urothelial carcinoma (UTUC) and to evaluate its association with clinical outcomes. METHODS: This multicenter retrospective study included 732 patients treated with radical nephroureterectomy for UTUC. HER2 expression was assessed using immunohistochemistry and scored according to the HercepTest: Scores of 0 or 1 were considered negative and 2 or 3 as positive. To qualify for 2 scoring, complete membrane staining of more than 10 % of tumor cells at a moderate intensity had to be observed. RESULTS: HER2 was overexpressed in 262 (35.8 %) patients. It was associated with pathologic characteristics such as more advanced T stage (p < 0.001), presence of lymph node metastasis (p = 0.006), high-grade tumor (p < 0.001), tumor necrosis (p = 0.01) and lymphovascular invasion (p = 0.02). Patients with HER2 overexpression had a 1.66-fold increased risk of experiencing disease recurrence (95 % CI 1.24-2.24, p = 0.001), 1.55-fold increased risk of death (95 % CI 1.21-1.99, p = 0.001) and 1.81-fold increased risk of cancer-specific death (95 % CI 1.33-2.48, p < 0.001). On multivariable analysis that adjusted for the effects of standard clinicopathologic variables, HER2 overexpression remained associated with disease recurrence (p = 0.04), overall (p = 0.02) and cancer-specific mortality (p = 0.02). CONCLUSIONS: Approximately, one-third of UTUC patients overexpressed HER2. HER2 overexpression was associated with features of clinically and biologically aggressive disease as well as prognosis. HER2 may represent a good marker for therapeutic risk stratification and potentially a target for therapy in some UTUC tumors.

Prognostic Significance of Preoperative Circulating Monocyte Count in Patients With Breast Cancer: Based on a Large Cohort Study.

Growing evidence showed that inflammation response plays an important role in cancer development and progression, and absolute lymphocyte count (ALC), absolute monocyte count (AMC), and lymphocyte to monocyte ratio (LMR) have been used as parameters of systemic inflammation in several tumors. In this study, we evaluated the prognostic significance of preoperative ALC, AMC and LMR in breast cancer and 2000 patients between January 2002 and December 2008 at Sun Yat-Sen University Cancer Center were enrolled. Patients were grouped by the cut-off value according to the receiver operating characteristics (ROC) curve analysis. Kaplan-Meier analysis showed that patients with elevated AMC levels (>0.48 × 10/L) had shorter overall survival (OS, P < 0.001). In multivariate analysis, preoperative AMC was identified as an independent prognostic parameter for OS in breast cancer patients (hazard ratio = 1.374, 95% confidence interval: 1.045-1.807). Subgroup analyses revealed that AMC was an unfavorable prognostic factor in stage II-III breast cancer patients and Luminal B, human epithelial growth factor receptor-2 overexpressing subtype, and triple-negative breast cancer (all P < 0.05). Additionally, the prognostic value of ALC and LMR could not be proven in the current study. Preoperative AMC may serve as an easily available and low-priced parameter to predict the outcomes of breast cancer.

Role of G protein-coupled receptors (GPCR), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), heparin-binding epidermal growth factor-like growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) in trenbolone acetate-stimulated bovine satellite cell proliferation.

Implanting cattle with steroids significantly enhances feed efficiency, rate of gain, and muscle growth. However, the mechanisms responsible for these improvements in muscle growth have not been fully elucidated. Trenbolone acetate (TBA), a testosterone analog, has been shown to increase proliferation rate in bovine satellite cell (BSC) cultures. The classical genomic actions of testosterone have been well characterized; however, our results indicate that TBA may also initiate a quicker, nongenomic response that involves activation of G protein-coupled receptors (GPCR) resulting in activation of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) that release membrane-bound heparin-binding epidermal growth factor-like growth factor (hbEGF), which then binds to and activates the epidermal growth factor receptor (EGFR) and/or erbB2. Furthermore, the EGFR has been shown to regulate expression of the IGF-1 receptor (IGF-1R), which is well known for its role in modulating muscle growth. To determine whether this nongenomic pathway is potentially involved in TBA-stimulated BSC proliferation, we analyzed the effects of treating BSC with guanosine 5'-O-2-thiodiphosphate (GDPßS), an inhibitor of all GPCR; a MMP2 and MMP9 inhibitor (MMPI); CRM19, a specific inhibitor of hbEGF; AG1478, a specific EGFR tyrosine kinase inhibitor; AG879, a specific erbB2 kinase inhibitor; and AG1024, an IGF-1R tyrosine kinase inhibitor on TBA-stimulated proliferation rate (H-thymidine incorporation). Assays were replicated at least 9 times for each inhibitor experiment using BSC cultures obtained from at least 3 different animals. Bovine satellite cell cultures were obtained from yearling steers that had no previous exposure to androgenic or estrogenic compounds. As expected, BSC cultures treated with 10 n TBA showed ( < 0.05) increased proliferation rate when compared with control cultures. Additionally, treatment with 5 ng hbEGF/mL stimulated proliferation in BSC cultures ( < 0.05). Treatment with GDPßS, MMPI, CRM197, AG1024, AG1478, and/or AG879 all suppressed ( < 0.05) TBA-induced increases in proliferation. These data indicate that TBA likely initiates a nongenomic response involving GPCR, MMP2 and MMP9, hbEGF, EGFR, erbB2, and IGF-1R, which may play a role in TBA-mediated increases in BSC proliferation.

GATA-binding protein 3, gross cystic disease fluid protein-15 and mammaglobin have distinct prognostic implications in different invasive breast carcinoma subgroups.

AIMS: To evaluate the prognostic significance of GATA-binding protein 3 (GATA-3), gross cystic disease fluid protein-15 (GCDFP-15) and mammaglobin (MGB) in invasive breast carcinomas (IBCs). METHODS AND RESULTS: GATA-3, GCDFP-15 and MGB were expressed in 37.9% (370/976), 26.0% (254/978) and 35.3% (348/986) of this cohort of 1017 IBCs, respectively. GCDFP-15 was an independent favourable prognostic factor in all cases [disease-free survival (DFS), hazard ratio (HR) 0.587, P = 0.049; overall survival (OS), HR 0.512, P = 0.049], as well as in oestrogen receptor (ER)-negative (DFS, HR 0.353, P = 0.012; OS, HR 0.310, P = 0.017) and HER2-positive (DFS, HR 0.279, P = 0.036; OS, HR 0.235, P = 0.050) cases; it also refined the prognostication of molecular apocrine cancers. GATA-3 and MGB did not show any prognostic significance. CONCLUSIONS: The commonly used breast carcinoma biomarkers vary in their prognostic implications. GCDFP-15 independently indicated a favourable prognosis, especially in ER-negative, HER2-positive and molecular apocrine cancers. GATA-3 and MGB were not associated with outcome.

Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors.

PURPOSE: To characterize the population pharmacokinetics (PK) of pertuzumab across clinical trials in a variety of solid tumors, evaluate the potential impact of patient characteristics on PK, and confirm the appropriateness of the fixed (non-weight-based) dose. METHODS: Pertuzumab concentration data collected following intravenous administration during eleven phase I/II studies and the pivotal phase III trial CLEOPATRA were analyzed using nonlinear mixed-effects modeling. The potential impact of patient and laboratory characteristics and HER2 target-related variables on pertuzumab PK were investigated in a covariate analysis. The final model was used to confirm selection of fixed, non-weight-based dosing of pertuzumab, and to compare pertuzumab PK in CLEOPATRA with the other studies. RESULTS: The analysis included 4,525 serum concentration measurements from 481 patients with solid tumors. Pertuzumab PK in the 2-25 mg/kg dose range was described by a two-compartment linear model with first-order elimination. The elimination clearance and central compartment volume were 0.235 L/day, and 3.11 L, respectively, and the terminal elimination half-life was 18.0 days. Baseline serum albumin and lean body weight had statistically significant effects on pertuzumab clearance; however, simulations showed that the magnitude of their effects on pertuzumab exposure was minimal compared with overall variability and was not clinically relevant. Thus, variations in these factors do not require dose adjustments. CONCLUSIONS: The fixed, non-weight-based dosing of pertuzumab, 840 mg loading dose followed by a 420 mg maintenance dose every 3 weeks, in patients with the solid tumors in this analysis is well supported by the population pharmacokinetic modeling and simulation results.

Epigallocatechin 3-O-gallate induces 67 kDa laminin receptor-mediated cell death accompanied by downregulation of ErbB proteins and altered lipid raft clustering in mammary and epidermoid carcinoma cells.

Since the administration of synthetic medicines is associated with drug resistance and undesired side effects, utilization of natural compounds could be an alternative and complementary modality to inhibit or prevent the development of tumors. Epigallocatechin 3-O-gallate (EGCG, 1), the major flavan component of green tea, and genistein (2), a soy isoflavonoid, are known to have chemopreventive and chemotherapeutic effects against cancer. This study demonstrated that both flavonoids inhibit cell proliferation, an effect enhanced under serum-free conditions. Compound 1, but not 2, induced downregulation of ErbB1 and ErbB2 in mammary and epidermoid carcinoma cells, and its inhibitory effect on cell viability was mediated by the 67 kDa laminin receptor (67LR). While 1 was superior in inducing cell death, 2 was more efficient in arresting the tumor cells in the G2/M phase. Furthermore, number and brightness analysis revealed that 1 decreased the homoclustering of a lipid raft marker, glycosylphosphatidylinositol-anchored GFP, and it also reduced the co-localization between lipid rafts and 67LR. The main conclusion made is that the primary target of 1 may be the lipid raft component of the plasma membrane followed by secondary changes in the expression of ErbB proteins. Compound 2, on the other hand, must have other unidentified targets.

Cardioprotective effect of ß-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure.

BACKGROUND: Chemotherapy with trastuzumab and anthracycline is associated with incident heart failure (HF) in patients with breast cancer. We hypothesized that continuous incidental use of ß-blocker agents (BB) was protective against HF in patients without established structural heart disease who were receiving trastuzumab and anthracycline. METHODS AND RESULTS: We identified 920 consecutive patients with breast cancer (age 52.3±11.0 years) with normal ejection fraction before receiving trastuzumab and anthracycline therapy at our institution between 2005 and 2010. Using a propensity score and a greedy 5 to 1 digit-matching algorithm, 106 of these patients on continuous BB during cancer treatment were matched with 212 patients from the same pool with similar characteristics but not on continuous BB. During a median follow-up of 3.2±2.0 years, 32 incident HF admissions were identified in these 318 patients with breast cancer, whereas 28 cancer-related (noncardiac) deaths occurred before any incident HF. Cumulative incidence regression models and cause-specific hazards of new HF events were estimated from competing risk Cox models of time-dependent covariates. Although trastuzumab therapy showed significant association with incident HF, independent of anthracycline-related cardiotoxicity (hazard ratio, 9.0; 95% confidence interval, 3.0-27.0; P<0.0001), continuous use of BB was associated with lower risk of new HF events (hazard ratio, 0.2; 95% confidence interval, 0.1-0.5; P=0.003). CONCLUSIONS: Coincidental, continuous use of BB is associated with lower incidence of HF in patients with breast cancer and normal baseline ejection fraction in a competing risk framework, and after matching for demographics, clinical, and cancer-related treatment characteristics. Prospective randomized clinical trials to validate these findings are warranted.

Breed-related differences in altered BRCA1 expression, phenotype and subtype in malignant canine mammary tumors.

BRCA1 is a high-penetrance breast cancer susceptibility gene and BRCA1-associated breast cancer has a high familial prevalence that is more common among certain populations of humans. A similar high prevalence also exists for canine mammary tumors (CMTs) and the objective of this study was to determine the breed-related differences in malignant CMTs. Comparative analyses of the expression of various prognostic factors for CMTs, including BRCA1, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) were conducted on 139 malignant CMT cases from five breeds with the highest prevalence of CMTs in Korea. Significant breed-related differences were observed in the expression of BRCA1 (P=0.003), histological grade (P=0.038), and extensive lymphatic invasion (P=0.042). The Shih Tzu breed had the highest proportion of dogs with malignant CMT and strong overexpression of BRCA1. Cytoplasmic and membranous expression of BRCA1 was associated with the ER negative (P=0.004), PR negative (P=0.046), and triple negative (ER, PR, and HER-2 negative; P=0.016) phenotype and the basal-like molecular subtype (P=0.019) in Shih Tzu dogs. Since these features are similar to BRCA1-related human breast cancer, dogs with BRCA1-associated CMT, particularly Shih Tzu dogs, may serve as a suitable spontaneous model, although additional molecular studies are needed.