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Supplementary Figure S1.

Purpose: To investigate expression, regulation, potential role and targets of miR-195 and miR-497 in breast cancer.Experimental Design: The expression patterns of miR-195 and miR-497 were initially examined in breast cancer tissues and cell lines by Northern blotting and quantitative real-time PCR. Combined bisulfite restriction analysis and bisulfite sequencing were carried out to study the DNA methylation status of miR-195 and miR-497 genes. Breast cancer cells stably expressing miR-195 and miR-497 were established to study their role and targets. Finally, normal, fibroadenoma and breast cancer tissues were employed to analyze the correlation between miR-195/497 levels and malignant stages of breast tumor tissues.Results: MiR-195 and miR-497 were significantly downregulated in breast cancer. The methylation state of CpG islands upstream of the miR-195/497 gene was found to be responsible for the downregulation of both miRNAs. Forced expression of miR-195 or miR-497 suppressed breast cancer cell proliferation and invasion. Raf-1 and Ccnd1 were identified as novel direct targets of miR-195 and miR-497. miR-195/497 expression levels in clinical specimens were found to be correlated inversely with malignancy of breast cancer.Conclusions: Our data imply that both miR-195 and miR-497 play important inhibitory roles in breast cancer malignancy and may be the potential therapeutic and diagnostic targets. Clin Cancer Res; 17(7); 1722–30. ©2011 AACR.

Breast cancer is the second highest cause of carcinoma-related death caused by distant metastasis in women. Estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and progesterone receptor (PR) are three classified makers of breast cancer, which are defined as ER + , HER2 + , and the most serious ER − PR − HER2− (triple-negative). It is well known that ErbB2 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2) plays an important part in breast cancer. However, the molecular mechanisms underlying ErbB2 action needs to be well studied. In this report, we discovered that the decreased expression levels of miR-34a were inversely correlated with the increased ErbB2 levels in breast cancer. A luciferase reporter assay was done to understand the potential correlation between ErbB2 and miR-34a. Over-expression of miR-34a reduces ErbB2 expression and suppresses breast cancer cell invasion and growth in vitro. What's more, reduced expression of ErbB2 inhibits breast Cancer cell proliferation and re-expression of ErbB2 reversed miR-34a-dependent tumor suppression. Meanwhile, miR-34a levels were correlated inversely with breast cancer malignancy. Our study demonstrates that miR-34a, like ErbB2, might be a diagnostic target in breast cancer.

MAP kinase interacting serine/threonine kinase 2 (MKNK2) belongs to the protein kinase superfamily which phosphorylates and activates eukaryotic initiation factor 4E (elF4E), a rate limiting factor in protein synthesis that enhances the translation of some proteins involved in cell cycle, apoptosis and angiogenesis regulation. In this study, we found that the expression levels of MKNK2 are inversely correlated with the expression levels of miR-125b in human breast cancer development. We showed that miR-125b inhibited tumor cell growth and invasion by regulating MKNK2 at posttranscriptional level. Thus, both miR-125b and MKNK2 could be therapeutically targeted in breast cancer.

Breast cancer is the second highest cause of carcinoma-related death caused by distant metastasis in women. Estrogen receptor (ER), human epidermal growth factor receptor 2, (HER2) and progesterone receptor (PR) are three classified makers of breast cancer, which are defined as ER+, HER2+, and the most serious ER-PR-HER2- (triple-negative). It is well known that ErbB2 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2) plays an important part in breast cancer. However, the molecular mechanisms underlying ErbB2 action needs to be well studied. In this report, we discovered that the decreased expression levels of miR-34a were inversely correlated with the increased ErbB2 levels in breast cancer. A luciferase reporter assay was done to understand the potential correlation between ErbB2 and miR-34a. Over-expression of miR-34a reduces ErbB2 expression and suppresses breast cancer cell invasion and growth in vitro. What's more, reduced expression of ErbB2 inhibits breast Cancer cell proliferation and re-expression of ErbB2 reversed miR-34a-dependent tumor suppression. Meanwhile, miR-34a levels were correlated inversely with breast cancer malignancy. Our study demonstrates that miR-34a, like ErbB2, might be a diagnostic target in breast cancer.

Angiogenesis has been found as an attractive target for drug therapy as it is necessary for tumor growth. Accumulating evidences show that microRNAs (miRNAs), which are a group of highly conserved, single-stranded, short non-coding RNAs, play important roles through directly targeting angiogenic factors and protein kinases. The purpose of this study is to investigate the role of miR-195 in breast cancer development and angiogenesis through targeting IRS1. We show that miR-195 is inversely related with Insulin receptor substrate 1 (IRS1) in both breast cancer cells and breast cancer tissues. Induction of miR-195 could suppress IRS1 protein expression through binding to its 3'UTR regions either by transfection with miR-195 oligo or by infection with lentivirus encoding miR-195 gene. Moreover, re-expression of IRS1 reverses miR-195-mediated repression of tumor cell growth and miR-195 inhibits tumor angiogenesis through suppressing IRS1-VEGF axis. These data suggest that miR-195 mimics are potential therapeutic agents for breast cancer diagnose.

MiR-145 is known as a tumor suppressor in numerous human cancers. However, its role in tumor angiogenesis remains poorly defined. In this study, we found that miR-145 was significantly downregulated in breast cancer tissues by using 106 cases of normal and cancer tissues as well as in breast cancer cells. MiR-145 exhibited inhibitory role in tumor angiogenesis, cell growth and invasion and tumor growth through the post-transcriptional regulation of the novel targets N-RAS and VEGF-A. In addition, we provide evidence that the expression levels of miR-145 correlate inversely with malignancy stages of breast tumors, although there is no association between miR-145 levels and hormone receptor levels in breast cancer. Taken together, these results demonstrate that miR-145 plays important inhibitory role in breast cancer malignancy by targeting N-RAS and VEGF-A, which may be potential therapeutic and diagnostic targets.

Phylogenetic combinatorics is a branch of discrete applied mathematics concerned with the combinatorial description and analysis of phylogenetic trees and related mathematical structures such as phylogenetic networks and tight spans. Based on a natural conceptual framework, the book focuses on the interrelationship between the principal options for encoding phylogenetic trees: split systems, quartet systems and metrics. Such encodings provide useful options for analyzing and manipulating phylogenetic trees and networks, and are at the basis of much of phylogenetic data processing. This book highlights how each one provides a unique perspective for viewing and perceiving the combinatorial structure of a phylogenetic tree and is, simultaneously, a rich source for combinatorial analysis and theory building. Graduate students and researchers in mathematics and computer science will enjoy exploring this fascinating new area and learn how mathematics may be used to help solve topical problems arising in evolutionary biology.

We investigate the dynamical behavior of spinodal decomposition in binary mixtures using a variation on the Rothman−Keller cellular automaton, in which particles of type A(B) move toward domains of greater concentration of A(B). Domain growth and system morphologies are determined via the pair correlation function, revealing that (i) the characteristic domain size grows as R(t) ≈ t1/3 and (ii) the configurations of the mixtures at different times are self-similar. These results did not change when different game rules were adopted, indicating that self-similarity and the 1/3 scaling law constitute fundamental properties of any diffusion-driven phase separation process. The same model also was applied to describe the mixing process, and, as expected, it was determined that the characteristic time was dependent on the square of a characteristic linear dimension of the system.

It is argued that the real impact of mathematics is its power to shape concepts that allow us to understand the real world by manipulating virtual worlds.

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