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Exposure to exercise following a breast cancer diagnosis is associated with reductions in the risk of recurrence. However, it is not known whether breast cancers within the same molecular-intrinsic subtype respond differently to exercise. Syngeneic mouse models of claudin-low breast cancer (i.e., EO771, 4TO7, and C3(1)SV40Tag-p16-luc) were allocated to a uniform endurance exercise treatment dose (forced treadmill exercise) or sham-exercise (stationary treadmill). Compared to sham-controls, endurance exercise treatment differentially affected tumor growth rate: 1- slowed (EO771), 2- accelerated (C3(1)SV40Tag-p16-luc), or 3- was not affected (4TO7). Differential sensitivity of the three tumor lines to exercise was paralleled by effects on intratumoral Ki-67, Hif1-α, and metabolic programming. Inhibition of Hif1-α synthesis by the cardiac glycoside, digoxin, completely abrogated exercise-accelerated tumor growth in C3(1)SV40Tag-p16-luc. These results suggest that intratumoral Hif1-α expression is an important determinant of claudin-low breast cancer adaptation to exercise treatment.

// Robert Jones 1 , Katrina Watson 1 , Anthony Bruce 1 , Sarah Nersesian 1 , Jenna Kitz 1 , Roger Moorehead 1 1 Department of Biomedical Science, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada Correspondence to: Roger Moorehead, email: rmoorehe@uoguelph.ca Keywords: microRNA, miR-200f, miR-200c, mammary tumors, claudin-low Received: August 15, 2016 Accepted: February 06, 2017 Published: March 02, 2017 ABSTRACT Claudin-low breast cancer is a relatively rare breast cancer subtype. These cancers are typically ER - /PR - /HER2 - and express high levels of mesenchymal genes as well as genes associated with inflammation, angiogenesis and stem cell function. In addition to alterations in gene expression, it was recently demonstrated that claudin-low breast cancers express very low levels of the miR-200 family of miRNAs. Given that each miRNA can regulate tens, hundreds or even thousands of genes, miRNAs are being evaluated as therapeutic targets. In this study we show that mammary tumors from MTB-IGFIR transgenic mice and cell lines derived from these tumors represent a model of human claudin-low breast cancer and murine claudin-low mammary tumors and cell lines express only very low levels of all five members of the miR-200 family. Reduced miR-200 family expression appears to be regulated via methylation as cells and tumors expressing low levels of miR-200 family members had higher levels of CpG methylation in a putative promoter region than tumors and cells expressing high levels of miR-200 family members. Re-expression of miR-200c in murine claudin-low mammary tumor cells inhibited tumor cell proliferation and colony formation in vitro and tumor growth in vivo . With respect to tumor growth in vivo , re-expression of miR-200c was associated with a reduction in tumor vasculature and expression of Flt1 and Vegfc . Therefore, miR-200c is an important regulator of mesenchymal tumor cell growth.

// Yirong Zhu 1 , Mark D. Aupperlee 2 , Yong Zhao 2 , Ying Siow Tan 2 , Erin L. Kirk 4 , Xuezheng Sun 4 , Melissa A. Troester 4, 5, 6 , Richard C. Schwartz 3 , Sandra Z. Haslam 2 1 Cell and Molecular Biology Program and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 2 Department of Physiology and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 3 Department of Microbiology and Molecular Genetics and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 4 Department of Epidemiology, University of North Carolina at Chapel Hill, NC, USA 5 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA 6 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA Correspondence to: Sandra Z. Haslam, email: shaslam@msu.edu Richard C. Schwartz, email: schwart9@msu.edu Keywords: dietary animal fat, breast cancer, puberty, adulthood, Trp53-null Received: July 22, 2016 Accepted: October 19, 2016 Published: November 04, 2016 ABSTRACT Premenopausal breast cancer is associated with increased animal fat consumption among normal weight, but not overweight women (Farvid et al., 2014). Our previous findings in obesity-resistant BALB/c mice similarly showed promotion of carcinogen-induced mammary tumorigenesis by a diet high in saturated animal fat (HFD). This effect was specific to pubertal versus adult HFD. This study identifies the effects of HFD during puberty versus adulthood in Trp53-null transplant BALB/c mice and investigates its mechanism of enhancing tumorigenesis. Either pubertal or adult HFD is sufficient to increase incidence of Trp53-null mammary tumors. Puberty-restricted HFD exposure promoted tumor cell proliferation, increased angiogenesis, and increased recruitment of total and M2 macrophages in epithelial tumors. Adult-restricted exposure to HFD similarly increased proliferation, angiogenesis, recruitment of total and M2 macrophages, and additionally reduced apoptosis. Adult HFD also increased incidence of spindle cell carcinomas resembling claudin-low breast cancer, and thus adult HFD in the Trp53-null transplantation system may be a useful model for human claudin low breast cancer. Importantly, these results on Trp53-null and our prior studies on DMBA-induced mammary tumorigenesis demonstrate a pubertal window of susceptibility to the promotional effects of HFD, indicating the potential of early life dietary intervention to reduce breast cancer risk.

// Miao Li 1 , Xi Li 2 , Yan Zhuang 3 , Yan Wang 4 , Matthew E. Burow 3 , Bridgette Collins-Burow 3 , Min Xue 5 , Chengjie Song 5 , Bin Shan 6 1 Department of Microbiology and Parasitology, College of Basic Medical Sciences, China Medical University, Shenyang, China 2 Department of Sports Medicine and Joint Surgery, The People’s Hospital of Liaoning Province, Shenyang, China 3 Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA 4 Department of Biological Engineering, Zunyi Medical College Zhuhai Campus, Zhuhai, China 5 Department of Physiology, Xuzhou Medical College, Xuzhou, China 6 Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University Spokane, Spokane, WA, USA Correspondence to: Miao Li, email: sendtolm@126.com Bin Shan, email: bin.shan@wsu.edu Keywords: breast cancer, extracellular matrix, three-dimensional organotypic culture, gene expression, homeobox gene Received: February 05, 2016 Accepted: June 29, 2016 Published: July 08, 2016 ABSTRACT The gene expression signatures of the molecular intrinsic subtypes of breast cancer are regulated by epigenetic mechanisms such as methylation of CpG islands in gene promoters. Epigenetic codes can be regulated by the tumor microenvironment. The Claudin-low subtype is associated with triple-negative invasive ductal carcinomas in patients. Herein we explored epigenetic regulation of gene expression in the Claudin-low breast cancer cells by extracellular matrix (ECM), a key component of the tumor microenvironment. We modeled attachment to ECM using laminin rich ECM three-dimensional organotypic culture (lrECM 3D). In 2D and lrECM 3D cultures we examined expression of the homeobox (HOX) genes that epigenetically regulated in development and cancer. We demonstrated induction of the selected HOX genes in lrECM 3D culture of the Claudin-low breast cancer cells MDA-MB-231 and Hs578T. In particular activation of HOXA9 expression in lrECM 3D culture required binding of bromodomain containing 4 to the HOXA9 promoter and involved CpG hypomethylation. Our findings warrant further investigation of the ECM-regulated epigenetic coding of gene expression in the Claudin-low breast cancer.

// Shreya Mitra 1 , Lorenzo Federico 1 , Wei Zhao 1 , Jennifer Dennison 1 , Tapasree Roy Sarkar 2 , Fan Zhang 1 , Vinita Takiar 3 , Kwai W. Cheng 4 , Sendurai Mani 5 , Ju Seog Lee 1 , Gordon B. Mills 1 1 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Center for Statistical Bioinformatics, Texas A&M University, College Station, TX, USA 3 Department of Radiation Oncology, University of Cincinnati, Cincinnati, OH, USA 4 Cardiac Catheterization Laboratory, Michael and DeBakey Medical Center, Houston, TX, USA 5 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Shreya Mitra, email: smitra@mdanderson.org Keywords: Rab25, Rab coupling protein, breast cancer, luminal B, claudin low Received: March 30, 2016 Accepted: May 10, 2016 Published: May 31, 2016 ABSTRACT The Rab GTPases regulate vesicular trafficking machinery that transports and delivers a diverse pool of cargo, including growth factor receptors, integrins, nutrient receptors and junction proteins to specific intracellular sites. The trafficking machinery is indeed a major posttranslational modifier and is critical for cellular homeostasis. Deregulation of this stringently controlled system leads to a wide spectrum of disorders including cancer. Herein we demonstrate that Rab25, a key GTPase, mostly decorating the apical recycling endosome, is a dichotomous variable in breast cancer cell lines with higher mRNA and protein expression in Estrogen Receptor positive (ER+ve) lines. Rab25 and its effector, Rab Coupling Protein (RCP) are frequently coamplified and coordinately elevated in ER+ve breast cancers. In contrast, Rab25 levels are decreased in basal-like and almost completely lost in claudin-low tumors. This dichotomy exists despite the presence of the 1q amplicon that hosts Rab25 across breast cancer subtypes and is likely due to differential methylation of the Rab25 promoter. Functionally, elevated levels of Rab25 drive major hallmarks of cancer including indefinite growth and metastasis but in case of luminal B breast cancer only. Importantly, in such ER+ve tumors, coexpression of Rab25 and its effector, RCP is significantly associated with a markedly worsened clinical outcome. Importantly, in claudin-low cell lines, exogenous Rab25 markedly inhibits cell migration. Similarly, during Snail-induced epithelial to mesenchymal transition (EMT) exogenous Rab25 potently reverses Snail-driven invasion. Overall, this study substantiates a striking context dependent role of Rab25 in breast cancer where Rab25 is amplified and enhances aggressiveness in luminal B cancers while in claudin-low tumors, Rab25 is lost indicating possible anti-tumor functions.