Microenvironmental factors in cell segregation and heterogeneity in breast cancer development

ABSTRACTWe analyzed a quantitative model that describes the epigenetic dynamics during the growth and evolution of an avascular tumor. A gene regulatory network (GRN) formed by a set of ten genes that are believed to play an important role in breast cancer development was kinetically coupled to the microenvironmental agents: glucose, estrogens and oxygen. The dynamics of spontaneous mutations was described by a Yule-Furry master equation whose solution represents the probability that a given cell in the tissue undergoes a certain number of mutations at a given time. We assumed that mutations rate is modified by nutrients spatial gradients. The tumor mass was grown by means of a cellular automata supplemented with a set of reaction diffusion equations that described the transport of the microenvironmental agents. By analyzing the epigenetic states space described by the GRN dynamics, we found three attractors that were identified with the cellular epigenetic states: normal, precancer and cancer. For two-dimensional (2D) and three-dimensional (3D) tumors we calculated the spatial distributions of the following quantities: (i) number of mutations, (ii) mutations of each gene and, (iii) phenotypes. Using estrogens as the principal microenvironmental agent that regulates cells proliferation process, we obtained the tumor shapes for different values of the estrogen consumption and supply rates. It was found that he majority of mutations occurred in cells that were located close to the 2D tumor perimeter or close to the 3D tumor surface. Also It was found that the occurrence of different phenotypes in the tumor are controlled by the levels of estrogen concentration since they can change the individual cell threshold and gene expression levels. All the results were consistently observed for 2D and 3D tumors.

Pilot Study to Determine Prevalence of CYP2B6*6,CYP2C19*2 and CYP2C19*3 in Breast Cancer Patients Versus Normal Healthy Controls Among Three Major Ethnic Groups in Singapore

Background: Breast cancer is the top cancer suffered by women worldwide and has been identified to be the greatest killer for women living in Singapore. Unfortunately, most of breast cancer cases were detected only at later stage of disease development. This has crippled the effort of breast cancer therapy. As early detection of breast cancer could greatly improve the outcome of breast cancer therapy, it is of utmost importance to identify relevant biomarkers at the primitive stage of breast cancer development before the transformation of normal breast cells into cancerous cells. These biomarkers provide important clues leading to an efficient and targeted treatment approach in breast cancer preventive care.Methods: 455 breast cancer patients were consented to join this study. Buccal swabs were collected for genotyping on CYP2B6*6, CYP2C19 *2 & CYP2C19*3. The genotyping data were then compared to data collected from healthy individuals. Clinical data were collected from patient notes and analysed. All the statistical analyses were done using SPSS statistical software, version 19.0. Chi-square or Fisher’s Exact test were performed to examine the difference between subject’s characteristics for categorical variables and One-Way Anova was performed to assess age difference across alleles of CYP2B6*6, CYP2C19*2 and CYP2C19*3. Binary logistics regression was performed to identify demographic factors associated with breast cancer.Results: We reported thatCYP2B6*6 could be a risk factor leading to earlier onset of breast cancer among Indian population with OR found to be 1.69 (95% C.I.= 0.549-5.191, p=0.359). In the case of CYP2C19*2, OR is 1.57 for Malay (95% C.I. = 0.696-3.522, p=0.278); 1.15 for Chinese population (95% C.I. =0.862-1.545, p=0.335) and 1.03 for Indian (95% C.I. =0.301-3.496, p=0.968). CYP2C19*3 OR in Chinese population is 1.34 (95% C.I. =0.830-2.155, p=0.231) and 0.77 (95% C.I. =0.172-3.394, p=0.724) for Malay population. No CYP2C19*3 was detected in both cohorts of Indian patients and healthy controls. Conclusions: CYP2B6*6 and CYP2C19*2 polymorphisms may confer a risk for breast cancer development in Singaporean breast cancer patients. This is an exploratory study to identify potential breast cancer susceptibility gene polymorphisms, a bigger sample size study could be done to corroborate these findings in future studies.

miR-183-5p Aggravates Breast Cancer Development via Mediation of RGS2

This study mainly explores how miR-183-5p pertains to breast cancer (BC) development. Functional assays were employed to test impacts of miR-183-5p in this cancer. Targeting between RGS2 and miR-183-5p was examined with dual-luciferase assay, and how their interaction pertains to cancer progression was further unraveled. miR-183-5p level was noticeably high in cancer tissue/cells. Overexpressing miR-183-5p could remarkably deteriorate cancer progression. The regulatory gene RGS2 levels was markedly low in BC, and two genes we researched were negatively correlated. It was uncovered by rescue assay that miR-183-5p/RGS2 axis mediated tumor-relevant behaviors in BC. Altogether, miR-183-5p aggravates BC development via mediation of RGS2. miR-183-5p supplies a promising target for BC therapy.

Fluid Flow Stimulation Modulates Expression of S100 Genes in Normal Breast Epithelium and Breast Cancer

Introduction S100 proteins are intracellular calcium ion sensors that participate in cellular processes, some of which are involved in normal breast functioning and breast cancer development. Despite several S100 genes being overexpressed in breast cancer, their roles during disease development remain elusive. Human mammary epithelial cells (HMECs) can be exposed to fluid shear stresses and implications of such interactions have not been previously studied. The goal of this study was to analyze expression profiles of S100 genes upon exposing HMECs to fluid flow. Methods HMECs and breast cancer cell lines were exposed to fluid flow in a parallel-plate bioreactor system. Changes in gene expression were quantified using microarrays and qPCR, gene-gene interactions were elucidated using network analysis, and key modified genes were examined in three independent clinical datasets. Results S100 genes were among the most upregulated genes upon flow stimulation. Network analysis revealed interactions between upregulated transcripts, including interactions between S100P, S100PBP, S100A4, S100A7, S100A8 and S100A9. Overexpression of S100s was also observed in patients with early stage breast cancer compared to normal breast tissue, and in most breast cancer patients. Finally, survival analysis revealed reduced survival times for patients with elevated expression of S100A7 and S100P. Conclusion This study shows that exposing HMECs to fluid flow upregulates genes identified clinically to be overexpressed during breast cancer development, including S100A7 and S100P. These findings are the first to show that S100 genes are flow-responsive and might be participating in a fundamental adaptation pathway in normal tissue that is also active in breast cancer.

An Updated Comprehensive Review on Vitamin A and Carotenoids in Breast Cancer: Mechanisms, Genetics, Assessment, Current Evidence, and Future Clinical Implications

Vitamin A and carotenoids are fat-soluble micronutrients that play important role as powerful antioxidants modulating oxidative stress and cancer development. Breast cancer is the most common malignancy in women. As the risk of breast cancer is dependent on various lifestyle factors such as dietary modifications, there is increasing interest surrounding the anti-cancerous properties of vitamin A and carotenoids. Despite the suggested protective roles of vitamin A and carotenoids in breast cancer development, their clinical application for the prevention and treatment of breast cancer is limited. In this narrative review, we discuss the roles of vitamin A and carotenoids along with the evaluation method of vitamin A status. We also exhibit the association of genetic variations involved in metabolism of vitamin A and carotenoids with cancers and other diseases. We demonstrate the epidemiological evidence for the relationship of vitamin A and carotenoids with breast cancer risk, their effects on cancer mechanism, and the recent updates in clinical practice of vitamin A or carotenoids as a potential therapeutic agent against breast cancer. This review provides insight into the preventive and therapeutic roles of vitamin A and carotenoids in breast cancer development and progression.

The Reactivity of Human and Equine Estrogen Quinones towards Purine Nucleosides

Conjugated estrogen medicines, which are produced from the urine of pregnant mares for the purpose of menopausal hormone replacement therapy (HRT), contain the sulfate conjugates of estrone, equilin, and equilenin in varying proportions. The latter three steroid sex hormones are highly similar in molecular structure as they only differ in the degree of unsaturation of the sterane ring “B”: the cyclohexene ring in estrone (which is naturally present in both humans and horses) is replaced by more symmetrical cyclohexadiene and benzene rings in the horse-specific (“equine”) hormones equilin and equilenin, respectively. Though the structure of ring “B” has only moderate influence on the estrogenic activity desired in HRT, it might still significantly affect the reactivity in potential carcinogenic pathways. In the present theoretical study, we focus on the interaction of estrogen orthoquinones, formed upon metabolic oxidation of estrogens in breast cells with purine nucleosides. This multistep process results in a purine base loss in the DNA chain (depurination) and the formation of a “depurinating adduct” from the quinone and the base. The point mutations induced in this manner are suggested to manifest in breast cancer development in the long run. We examine six reactions between deoxyadenosine and deoxyguanosine as nucleosides and estrone-3,4-quinone, equilin-3,4-quinone, and equilenin-3,4-quinone as mutagens. We performed DFT calculations to determine the reaction mechanisms and establish a structure–reactivity relationship between the degree of unsaturation of ring “B” and the expected rate of DNA depurination. As quinones might be present in the cytosol in various protonated forms, we introduce the concept of “effective barriers” to account for the different reactivity and different concentrations of quinone derivatives. According to our results, both equine estrogens have the potential to facilitate depurination as the activation barrier of one of the elementary steps (the initial Michael addition in the case of equilenin and the rearomatization step in the case of equilin) significantly decreases compared to that of estrone. We conclude that the appearance of exogenous equine estrogen quinones due to HRT might increase the risk of depurination-induced breast cancer development compared to the exposure to endogenous estrone metabolites. Still, further studies are required to identify the rate-limiting step of depurination under intracellular conditions to reveal whether the decrease in the barriers affects the overall rate of carcinogenesis.