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We evaluated if standard hormonal therapy (HT) could be improved by the addition of mammalian target of rapamycin inhibitors (mTOR-I) in metastatic luminal breast cancer. A meta-analysis on 4 phase II-III randomized clinical trials was performed. Pooled hazard ratio (HR) for progression free survival (PFS)/ time to progression (TTP) was 0.62 in favor of mTOR-I+HT arm (95% confidence interval [CI] 0.55-0.70; p

// Montserrat Perez-Salvia 1 , Laia Simo-Riudalbas 1 , Pere Llinas-Arias 1 , Laura Roa 1 , Fernando Setien 1 , Marta Soler 1 , Manuel Castro de Moura 1 , James E. Bradner 2 , Eva Gonzalez-Suarez 1 , Catia Moutinho 1 and Manel Esteller 1, 3, 4 1 Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain 2 Novartis Institutes for Biomedical Research, Cambridge, MA, USA 3 Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain 4 Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Catalonia, Spain Correspondence to: Catia Moutinho, email: cmoutinho@idibell.cat Manel Esteller, email: mesteller@idibell.cat Keywords: luminal breast cancer, bromodomain inhibitor, C-MYC, JQ1, mice model Received: February 28, 2017 Accepted: May 04, 2017 Published: May 29, 2017 ABSTRACT BET bromodomain inhibitors, which have an antitumoral effect against various solid cancer tumor types, have not been studied in detail in luminal breast cancer, despite the prevalence of this subtype of mammary malignancy. Here we demonstrate that the BET bromodomain inhibitor JQ1 exerts growth-inhibitory activity in human luminal breast cancer cell lines associated with a depletion of the C-MYC oncogene, but does not alter the expression levels of the BRD4 bromodomain protein. Interestingly, expression microarray analyses indicate that, upon JQ1 administration, the antitumoral phenotype also involves downregulation of relevant breast cancer oncogenes such as the Breast Carcinoma-Amplified Sequence 1 (BCAS1) and the PDZ Domain-Containing 1 (PDZK1). We have also applied these in vitro findings in an in vivo model by studying a transgenic mouse model representing the luminal B subtype of breast cancer, the MMTV-PyMT, in which the mouse mammary tumor virus promoter is used to drive the expression of the polyoma virus middle T-antigen to the mammary gland. We have observed that the use of the BET bromodomain inhibitor for the treatment of established breast neoplasms developed in the MMTV-PyMT model shows antitumor potential. Most importantly, if JQ1 is given before the expected time of tumor detection in the MMTV-PyMT mice, it retards the onset of the disease and increases the survival of these animals. Thus, our findings indicate that the use of bromodomain inhibitors is of great potential in the treatment of luminal breast cancer and merits further investigation.

// Katarzyna Szarc vel Szic 1, 4 , Ken Declerck 1 , Rene A.J. Crans 1, 3 , Jolien Diddens 1 , David B. Scherf 2 , Clarissa Gerhauser 2 and Wim Vanden Berghe 1 1 Laboratory of Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium 2 Workgroup Cancer Chemoprevention and Epigenomics, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Current address: Laboratory for GPCR Expression and Signal Transduction (L-GEST), Department of Biochemistry and Microbiology, University of Ghent, Ghent, Belgium 4 Current address: Division of Hematology, Oncology and Stem Cell Transplantation, Center for Translational Cell Research, The University Medical Center Freiburg, Freiburg, Germany Correspondence to: Wim Vanden Berghe, email: wim.vandenberghe@uantwerpen.be Keywords: triple negative breast cancer, luminal breast cancer, epigenetics, Withaferin A, DNA methylation Received: February 15, 2016 Accepted: March 30, 2017 Published: April 13, 2017 ABSTRACT Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2’-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 ( ADAM8 ), urokinase-type plasminogen activator ( PLAU ), tumor necrosis factor (ligand) superfamily, member 12 ( TNFSF12 ), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1 ), or mitochondrial metabolism (malic enzyme 3, ME3 ). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU , ADAM8 , TNSF12 , GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.

In this study, we compared the blood serum levels of circulating cell-free and exosomal microRNAs, and their involvement in the molecular subtypes of breast cancer patients. Our analyses on cell-free miR-101, miR-372 and miR-373 were performed in preoperative blood serum of 168 patients with invasive breast cancer, 19 patients with benign breast diseases and 28 healthy women. MicroRNAs were additionally quantified in exosomes of 50 cancer patients and 12 healthy women from the same cohort. Relative concentrations were measured by quantitative TaqMan MicroRNA assays and correlated to clinicopathological risk factors. The concentrations of cell-free miR-101 (p=0.013) and miR-373 (p=0.024) were significantly different between patients with breast cancer and benign tumors. A prevalence of miR-101, miR-372 and miR-373 were found in exosomes. The levels of circulating exosomal (but not cell-free) miR-373 were higher in triple negative than luminal carcinomas (p=0.027). Also, estrogen-negative (p=0.021) and progesterone-negative (p=0.01) tumors displayed higher concentrations of exosomal miR-373 than patients with hormone-receptor positive tumors. Overexpression of miR-373 by transfection of MCF-7 cells showed downregulated protein expression of the estrogen receptor, and inhibition of apoptosis induced by camptothecin. Our data indicate that serum levels of exosomal miR-373 are linked to triple negative and more aggressive breast carcinomas.

// Wei Sun 1, 2, 3, * , Yi-Zhou Jiang 1, 2, 3, * , Yi-Rong Liu 1, 2, 3, * , Ding Ma 1, 2, 3 , Zhi-Ming Shao 1, 2, 3, 4 1 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China 2 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, P.R. China 3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China 4 Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China * These authors contributed equally to this work Correspondence to: Zhi-Ming Shao, e-mail: zhimingshao@yahoo.com Keywords: nomogram, luminal breast cancer, overall survival, breast cancer-specific survival Received: December 02, 2015 Accepted: February 13, 2016 Published: March 07, 2016 ABSTRACT Luminal breast cancer constitutes a group of highly heterogeneous diseases with a sustained high risk of late recurrence. We aimed to develop comprehensive and practical nomograms to better estimate the long-term survival of luminal breast cancer. Patients with luminal breast cancer diagnosed between 1990 and 2006 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into the training ( n = 87,867) and validation ( n = 88,215) cohorts. The cumulative incidence function (CIF) and a competing-risks model were used to estimate the probability of breast cancer-specific survival (BCSS) and death from other causes. We integrated significant prognostic factors to build nomograms and subjected the nomograms to bootstrap internal validation and to external validation. We screened 176,082 luminal breast cancer cases. The 5- and 10-year probabilities of overall death were 0.089 and 0.202, respectively. The 5- and 10-year probabilities of breast cancer-specific mortality (BCSM) were 0.053 and 0.112, respectively. Nine independent prognostic factors for both OS and BCSS were integrated to construct the nomograms. The calibration curves for the probabilities of 5- and 10-year OS and BCSS showed excellent agreement between the nomogram prediction and actual observation. The C-indexes of the nomograms were high in both internal validation (0.732 for OS and 0.800 for BCSS) and external validation (0.731 for OS and 0.794 for BCSS). We established nomograms that accurately predict OS and BCSS for patients with luminal breast cancer. The nomograms can identify patients with higher risk of late overall mortality and BCSM, helping physicians in facilitating individualized treatment.