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Background Triple negative breast cancer (TNBC) is an aggressive neoplasia with no effective therapy. Our laboratory has developed a unique TNBC cell model presenting epithelial mesenchymal transition (EMT) a process known to be important for tumor progression and metastasis. There is increasing evidence showing that epigenetic mechanisms are involved in the activation of EMT. The objective of this study is to epigenetically reverse the process of EMT in TNBC by using DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi). Methods We evaluated the antitumor effect of three DNMTi and six HDACi using our TNBC cell model by MTT assay, migration and invasion assay, three dimensional culture, and colony formation assay. We then performed the combined treatment both in vitro and in vivo using the most potent DNMTi and HDACi, and tested the combined treatment in a panel of breast cancer cell lines. We investigated changes of EMT markers and potential signaling pathways associated with the antitumor effects. Results We showed that DNMTi and HDACi can reprogram highly aggressive TNBC cells that have undergone EMT to a less aggressive phenotype. SGI-110 and MS275 are superior to other seven compounds being tested. The combination of SGI with MS275 exerts a greater effect than single agent alone in inhibiting cell proliferation, motility, colony formation, and stemness of cancer cells. We also demonstrated that MS275 and the combination of SGI with MS275 exert in vivo antitumor effect. We revealed that the combined treatment synergistically reverses EMT through inhibiting EpCAM cleavage and WNT signaling, suppressing mutant p53, ZEB1, and EZH2, and inducing E-cadherin, apoptosis, as well as histone H3 tri-methylation. Conclusions Our study showed that DNMTi and HDACi exert antitumor activity in TNBC cells partially by epigenetically reprograming EMT. Our findings strongly suggest that TNBC is sensitive to epigenetic therapies. Therefore, we propose a new strategy to treat TNBC by using the combination of SGI-110 with MS275, which exerts superior antitumor effects by simultaneously targeting multiple pathways.

Genetic compositions of distinct human populations are different. How genomic variants influence many common and rare genetic diseases is always of great medical and anthropological interest, and understanding of genetic architectures of population groups in relation to diseases can advance our knowledge of medicine. Here, we have studied the genomic architecture of a group of Xavante Indians, an indigenous population in Brazil, and compared them with normal populations from the 1000 Genomes Projects. Principal component analysis (PCA) indicates that the Xavante Indians are genetically distinctive when compared to other ethnic groups. No incidence of breast cancer cases has ever been reported in the population, and polygenic risk analysis indicates extremely low breast cancer risk in this population when compared with germline TCGA (The Cancer Genome Atlas) breast cancer normal control samples. Low germinal mutation burden among this population is also observed. Our findings will help to deepen the understanding of breast cancer and might also provide new approaches to study the disease.

Background Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women. Methods Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues. Results Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns: (1) transient: genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing: genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant: genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues. Conclusions Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer.

Background Long non coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are not translated into proteins, but regulate the transcription of genes involved in different cellular processes, including cancer. Epidemiological analyses have demonstrated that parous women have a decreased risk of developing breast cancer in postmenopausal years if they went through a full term pregnancy in their early twenties. We here provide evidence of the role of BC200 in breast cancer and, potentially, in pregnancy’s preventive effect in reducing the lifetime risk of developing breast cancer. Methods Transcriptome analysis of normal breast of parous and nulliparous postmenopausal women revealed that several lncRNAs are differentially expressed in the parous breast. RNA sequencing of healthy postmenopausal breast tissue biopsies from eight parous and eight nulliparous women showed that there are 42 novel lncRNAs differentially expressed between these two groups. Screening of several of these 42 lncRNAs by RT-qPCR in different breast cancer cell lines, provided evidence that one in particular, lncEPCAM (more commonly known as BC200), was a strong candidate involved in cancer progression. Proliferation, migration, invasion and xerograph studies confirmed this hypothesis. Results The poorly studied oncogenic BC200 was selected to be tested in vitro and in vivo to determine its relevance in breast cancer and also to provide us with an understanding of its role in the increased susceptibility of the nulliparous women to cancer. Our results show that BC200 is upregulated in nulliparous women, and breast cancer cells and tissue. The role of BC200 is not completely understood in any of the breast cancer subtypes. We here provide evidence that BC200 has a role in luminal breast cancer as well as in the triple negative breast cancer subtype. Conclusion When overexpressed in luminal and triple negative breast cancer cell lines, BC200 shows increased proliferation, migration, and invasion in vitro. In vivo, overexpression of BC200 increased tumor size. Although treatment for cancer using lncRNAs as targets is in its infancy, the advancement in knowledge and technology to study their relevance in disease could lead to the development of novel treatment and preventive strategies for breast cancer.

Background: Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles. Objectives: Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer. Methods: We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 μg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age. Results: The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1-3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age. Conclusions: The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1-3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure.

Questions of reproducibility and efficacy of histologic malignancy grading relative to alternative proliferation index measurements for outcome prediction remain unanswered. Microsections of specimens from the Cooperative Breast Cancer Tissue Resource (CBCTR) were evaluated by seven pathologists for reproducibility of grade and classification. Nuclear figure classification was assessed using photographs. Grade was assigned by the Bloom–Richardson method, Nottingham modification. Proliferation index was evaluated prospectively by deoxyribose nucleic acid precursor uptake with thymidine (autoradiographic) or bromodeoxyuridine (immunohistochemical) labeling index using fresh tissue from 631 node-negative breast cancer patients accessioned at St Luke’s Hospital. A modified Nottingham–Bloom–Richardson grade was derived from histopathologic data. Median post-treatment observation was 6.4 years. Agreement on classification of nuclear figures (N=43) was less than good by kappa statistic (κ=0.38). Grade was moderately reproducible in four trials (N=10,10,19, 10) with CBCTR specimens (κ=0.50–0.59). Of components of Bloom–Richardson grade, agreement was least for nuclear pleomorphism (κ=0.37–0.50), best for tubularity (κ=0.57–0.83), and intermediate for mitotic count (κ=0.45–0.64). Bloom–Richardson grade was a univariate predictor of prognosis in node-negative St Luke’s patients, and was improved when mitotic count was replaced by labeling index (low, mid, or high). When labeling index was added to a multivariate model containing tumor size and vessel invasion, grade was no longer a significant predictor of tumor-specific relapse-free or overall survival. Mitotic index predicted best when intervals were lowered to 0–2, 3–10, and >10 mitotic figures per ten 0.18 mm2 high-power fields. We conclude that Nottingham–Bloom–Richardson grades remain only modestly reproducible. Prognostically useful components of grade are mitotic index and tubularity. The Nottingham–Bloom–Richardson system can be improved by lowering cutoffs for mitotic index and by counting 20–30 rather than 10 high-power fields. Measurement of proliferation index by immunohistochemically detectable markers will probably give superior prognostic results in comparison to grade.

Full-term pregnancy at an early age confers long-term protection against breast cancer. Published data shows a specific transcriptomic profile controlling chromatin remodeling that could play a relevant role in the pregnancy-induced protection. This process of chromatin remodeling, induced by the breast differentiation caused by the first full-term pregnancy, has mainly been measured by the expression level of genes individually considered. However, genes equally expressed during the process of chromatin remodeling may behave differently in their interaction with other genes. These changes at the gene cluster level could constitute an additional dimension of chromatin remodeling and therefore of the pregnancy-induced protection. In this research, we apply Information and Graph Theories, Differential Co-expression Network Analysis, and Multiple Regression Analysis, specially designed to examine structural and informational aspects of data sets, to analyze this question. Our findings demonstrate that, independently of the changes in the gene expression at the individual level, there are significant changes in gene–gene interactions and gene cluster behaviors. These changes indicate that the parous breast, through the process of early full-term pregnancy, generates more modules in the networks, with higher density, and a genomic structure performing additional and more complex functions than those found in the nulliparous breast.

Background Environmental estrogens are exogenous estrogen-mimicking compounds that can interfere with endogenous endocrine systems. Several of these endocrine disruptors have been shown to alter normal development and influence tumorigenesis in experimental models. N-butyl benzyl phthalate (BBP), a widely used plasticizer, is a well-known endocrine disruptor. The aim of this study was to elucidate the effect of prenatal exposure to BBP on the morphology, proliferative index, and genomic signature of the rat mammary gland at different ages. Methods In utero exposure was performed by gavage of pregnant Sprague Dawley CD rats with 120mg or 500mg BBP/kg/day from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50 and 100 days. The morphology and proliferative index of the mammary gland were studied from whole mount preparations and BrdU incorporation, respectively. Gene expression profile was assessed by microarrays. Several genes found differentially expressed and related to different functional categories were further validated by real time RT-PCR. Results Prenatal exposure of BBP induced delayed vaginal opening and changes in the post-natal mammary gland long after the end of the treatment, mainly by 35 days of age. Exposure to the high dose resulted in modifications in architecture and proliferative index of the mammary gland, mostly affecting the undifferentiated terminal end buds. Moreover, the expression profiles of this gland in the exposed rats were modified in a dose-dependent fashion. Analysis of functional categories showed that modified genes were related to immune function, cell signaling, proliferation and differentiation, or metabolism. Conclusions Our data suggest that in utero exposure to BBP induced a delayed pubertal onset and modified morphology of the mammary gland. These alterations were accompanied by modifications in gene expression previously associated with an increased susceptibility to carcinogenesis.

Purpose of Review Tennis elbow or lateral epicondylosis (LE) is a frequent cause of elbow pain affecting patients between 30 and 55 years of age. Although symptoms in most cases are self-limited, pain may persist and be refractory to conservative management. This review article will present evidence-based recommendations about conservative and interventional management options available for LE. Recent Findings Conservative management aimed at reducing pain with a short course of topical or oral anti-inflammatory medications, activity modification, correction of kinetic chain dysfunction, and the use of an exercise progression from isometric to eccentric exercise can be performed in the acute stage of the disease. If patients persist with pain and disability, nonsurgical interventional techniques such as corticosteroid injections, platelet-rich plasma injections, or other regenerative techniques such as extracorporeal shock wave therapy have shown evidence in improving patients’ pain in the subacute and chronic phases of the disease. Summary LE is the most common disorder of the arm causing disability. Treatment options range from conservative to surgical interventions. Continued research on nonsurgical interventional techniques that effectively treat pain and improve function in patients with LE is required to guide treatment.

The advances in the mathematical explanation of the dynamics underlying treated cancer has opened the door to the mathematical design of optimal therapies. In parallel, the improvements and cost reductions in experimentation and data analysis techniques have made the formulation of personalized therapies possible. However, the design of cancer therapies making use of optimal control theory has not fully considered this possibility in detail. In this paper we contribute to the existing literature by analyzing the diverse alternatives that optimal therapy models offer to design personalized treatments. Taking as the starting point the Chronic Myeloid Leukemia (CML) optimal therapy model in [25], we design personalized optimal therapy models for patients with: CML; CML with intrinsic and/or induced resistance to the administered drug; CML and suffering high drug toxicity and/or allergy to the administered drug; and CML with presence of adverse factors. Along the paper we show that the clinical and medical applicability -the ultimate objective of this biomathematical research- of our proposed personalized models relies on the joint and proper use of the implemented calibration, simulation, and mathematical approaches and techniques. All the theoretical results generated by our personalized optimal therapy models are corroborated by clinical evidence.