BREAST CANCER – CARCINOGENESIS, CELL GROWTH AND SIGNALING PATHWAYS Edited by Mehmet Gunduz and Esra Gunduz Breast Cancer – Carcinogenesis, Cell Growth and Signaling Pathways Edited by Mehmet Gunduz and Esra Gunduz Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access articles distributed under the Creative Commons Non Commercial Share Alike Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. 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ISBN 978-953-307-714-7 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface XI Part 1 Signaling Pathways (EGFR) 1 Chapter 1 EGFR-Ligand Signaling in Breast Cancer Metastasis: Recurring Developmental Themes 3 Nicole K. Nickerson, Jennifer L. Gilmore, Kah Tan Allen, David J. Riese II, Kenneth P. Nephew and John Foley Chapter 2 EGF Regulation of HRPAP20: A Role for Calmodulin and Protein Kinase C in Breast Cancer Cells 33 Manasi N. Shukla, Donna J. Buckley and Arthur R. Buckley Chapter 3 Endocytic Trafficking of the Epidermal Growth Factor Receptor in Transformed Cells 49 Brian P. Ceresa Chapter 4 HER-2 Signaling in Human Breast Cancer 73 Kathleen M. Woods Ignatoski Chapter 5 Brain Metastases Progression of Breast Cancer 87 Ala-Eddin Al Moustafa, Amber Yasmeen, Lina Ghabreau, Ali H. Mohamed and Amal Achkhar Chapter 6 Signal Transduction Pathways in Breast Cancer – Drug Targets and Challenges 109 Samar Azab and Ayman Al-Hendy Chapter 7 ErbB2/HER2: Its Contribution to Basic Cancer Biology and the Development of Molecular Targeted Therapy 139 Tadashi Yamamoto, Makoto Saito, Kentaro Kumazawa, Ayano Doi, Atsuka Matsui, Shiori Takebe, Takuya Amari, Masaaki Oyama and Kentaro Semba Chapter 8 Trastuzumab-Resistance and Breast Cancer 171 Milos Dokmanovic and Wen Jin Wu VI Contents Chapter 9 Targeting HER-2 Signaling Network: Implication in Radiation Response 205 In Ah Kim Part 2 Estrogen Receptors 219 Chapter 10 The Importance of Cell Growth and Division Cell Growth and Division Bởi: OpenStaxCollege So far in this chapter, you have read numerous times of the importance and prevalence of cell division While there are a few cells in the body that not undergo cell division (such as gametes, red blood cells, most neurons, and some muscle cells), most somatic cells divide regularly A somatic cell is a general term for a body cell, and all human cells, except for the cells that produce eggs and sperm (which are referred to as germ cells), are somatic cells Somatic cells contain two copies of each of their chromosomes (one copy received from each parent) A homologous pair of chromosomes is the two copies of a single chromosome found in each somatic cell The human is a diploid organism, having 23 homologous pairs of chromosomes in each of the somatic cells The condition of having pairs of chromosomes is known as diploidy Cells in the body replace themselves over the lifetime of a person For example, the cells lining the gastrointestinal tract must be frequently replaced when constantly “worn off” by the movement of food through the gut But what triggers a cell to divide, and how does it prepare for and complete cell division? The cell cycle is the sequence of events in the life of the cell from the moment it is created at the end of a previous cycle of cell division until it then divides itself, generating two new cells The Cell Cycle One “turn” or cycle of the cell cycle consists of two general phases: interphase, followed by mitosis and cytokinesis Interphase is the period of the cell cycle during which the cell is not dividing The majority of cells are in interphase most of the time Mitosis is the division of genetic material, during which the cell nucleus breaks down and two new, fully functional, nuclei are formed Cytokinesis divides the cytoplasm into two distinctive cells Interphase A cell grows and carries out all normal metabolic functions and processes in a period called G1 ([link]) G1 phase (gap phase) is the first gap, or growth phase in the cell cycle For cells that will divide again, G1 is followed by replication of the DNA, during the S phase The S phase (synthesis phase) is period during which a cell replicates its DNA 1/10 Cell Growth and Division Cell Cycle The two major phases of the cell cycle include mitosis (cell division), and interphase, when the cell grows and performs all of its normal functions Interphase is further subdivided into G1, S, and G2 phases After the synthesis phase, the cell proceeds through the G2 phase The G2 phase is a second gap phase, during which the cell continues to grow and makes the necessary preparations for mitosis Between G1, S, and G2 phases, cells will vary the most in their duration of the G1 phase It is here that a cell might spend a couple of hours, or many days The S phase typically lasts between 8-10 hours and the G2 phase approximately hours In contrast to these phases, the G0 phase is a resting phase of the cell cycle Cells that have temporarily stopped dividing and are resting (a common condition) and cells that have permanently ceased dividing (like nerve cells) are said to be in G0 The Structure of Chromosomes Billions of cells in the human body divide every day During the synthesis phase (S, for DNA synthesis) of interphase, the amount of DNA within the cell precisely doubles Therefore, after DNA replication but before cell division, each cell actually contains two copies of each chromosome Each copy of the chromosome is referred to as a sister chromatid and is physically bound to the other copy The centromere is the structure that attaches one sister chromatid to another Because a human cell has 46 chromosomes, during this phase, there are 92 chromatids (46 × 2) in the cell Make sure not to confuse the concept of a pair of chromatids (one chromosome and its exact copy attached during mitosis) and a homologous pair of chromosomes (two paired chromosomes which were inherited separately, one from each parent) ([link]) 2/10 Cell Growth and Division A Homologous Pair of Chromosomes with their Attached Sister Chromatids The red and blue colors correspond to a homologous pair of chromosomes Each member of the pair was separately inherited from one parent Each chromosome in the homologous pair is also bound to an identical sister chromatid, which is produced by DNA replication, and results in the familiar “X” shape Mitosis and Cytokinesis The mitotic phase of the cell typically takes between and hours During this phase, a cell undergoes two major processes First, it completes mitosis, during which the contents of the nucleus are equitably pulled apart and distributed between its two halves Cytokinesis then occurs, dividing the cytoplasm and cell body into two new cells Mitosis is divided into four major stages that take place after interphase ([link]) and in the following order: prophase, metaphase, anaphase, and telophase The process is then followed by cytokinesis 3/10 Cell Growth ...Research article Differences in the way a mammalian cell and yeast cells coordinate cell growth and cell-cycle progression Ian Conlon and Martin Raff Address: MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK. Correspondence: Martin Raff. E-mail: m.raff@ucl.ac.uk Abstract Background: It is widely believed that cell-size checkpoints help to coordinate cell growth and cell-cycle progression, so that proliferating eukaryotic cells maintain their size. There is strong evidence for such size checkpoints in yeasts, which maintain a constant cell-size distribution as they proliferate, even though large yeast cells grow faster than small yeast cells. Moreover, when yeast cells are shifted to better or worse nutrient conditions, they alter their size threshold within one cell cycle. Populations of mammalian cells can also maintain a constant size distribution as they proliferate, but it is not known whether this depends on cell-size checkpoints. Results: We show that proliferating rat Schwann cells do not require a cell-size checkpoint to maintain a constant cell-size distribution, as, unlike yeasts, large and small Schwann cells grow at the same rate, which depends on the concentration of extracellular growth factors. In addition, when shifted from serum-free to serum-containing medium, Schwann cells take many divisions to increase their size to that appropriate to the new condition, suggesting that they do not have cell-size checkpoints similar to those in yeasts. Conclusions: Proliferating Schwann cells and yeast cells seem to use different mechanisms to coordinate their growth with cell-cycle progression. Whereas yeast cells use cell-size checkpoints, Schwann cells apparently do not. It seems likely that many mammalian cells resemble Schwann cells in this respect. Published: 24 April 2003 Journal of Biology 2003, 2:7 The electronic version of this article is the complete one and can be found online at http://jbiol.com/content/2/1/7 Received: 2 December 2002 Revised: 6 March 2003 Accepted: 18 March 2003 Journal of Biology 2003, 2:7 Background Cell growth is as fundamental for organismal growth as cell division. Without cell growth, no organism can grow. Yet, compared to cell division, cell growth has been inexplicably neglected by cell biologists. Proliferating cells in culture tend to double their mass before each division [1], but it is not known how cell growth is coordinated with cell-cycle progres- sion to ensure that the cells maintain their size. We have been studying how this coordination is achieved in mammalian cells, using primary rat Schwann cells as a model system [2]. © 2003 Conlon and Raff, licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Open Access BioMed Central Journal of Biology Cell growth occurs in all phases of the cell cycle except M phase [1,3]. Yeast cells are thought to coordinate cell-cycle progression with cell growth through the action of cell-size checkpoints in G1 and/or G2, where the cell cycle can pause until the cell reaches an adequate size before pro- ceeding into S or M phase, respectively [4,5]. It is still uncertain how such checkpoints work, although there is evidence that the coupling of the threshold levels of certain cell-cycle activators to the general rate of translation plays a part [6,7]. It is also unknown whether mammalian cells have cell-size checkpoints, although it is widely believed that they do [3,7-9]. For most populations of proliferating eukaryotic cells in culture, including yeast cells and mammalian cells, the mean cell size remains constant over time, even though individual cells vary in size at division [10]. Thus, cells that are initially bigger or smaller than the mean after mitosis tend to return to the mean size over RESEARC H Open Access Functional characterization of Trip10 in cancer cell growth and survival Chia-Chen Hsu 1† , Yu-Wei Leu 1† , Min-Jen Tseng 1 , Kuan-Der Lee 2 , Tzen-Yu Kuo 1 , Jia-Yi Yen 1 , Yen-Ling Lai 1 , Yi-Chen Hung 1 , Wei-Sheng Sun 1 , Chien-Min Chen 3 , Pei-Yi Chu 4 , Kun-Tu Yeh 4 , Pearlly S Yan 5 , Yu-Sun Chang 6 , Tim H-M Huang 5 , Shu-Huei Hsiao 1* Abstract Background: The Cdc42-interacting protein-4, Trip10 (also known as CIP4), is a multi-domain adaptor protein involved in diverse cellular processes, which functions in a tissue-specific and cell lineage-specific manner. We previously found that Trip10 is highly expressed in estrogen receptor-expressing (ER + ) breast cancer cells. Estrogen receptor depletion reduced Trip10 expression by progressively increasing DNA methylation. We hypothesized that Trip10 functions as a tumor suppressor and may be involved in the malignancy of ER-negative (ER - ) breast cancer. To test this hypothesis and evaluate whether Trip10 is epigenetically regulated by DNA methylation in other cancers, we evaluated DNA methylation of Trip10 in liver cancer, brain tumor, ovarian cancer, and breast cancer. Methods: We applied methylation-specific polymerase chain reaction and bisulfite sequencing to determine the DNA methylation of Trip10 in various cancer cell lines and tumor specimens. We also overexp ressed Trip10 to observe its effect on colony formation and in vivo tumorigenesis. Results: We found that Trip10 is hypermethylated in brain tumor and breast cancer, but hypomethylated in liver cancer. Overexpressed Trip10 was associated with endogenous Cdc42 and huntingtin in IMR-32 brain tumor cells and CP70 ovarian cancer cells. However, overexpression of Trip10 promoted colony formation in IMR-32 cells and tumorigenesis in mice inoculated with IMR-32 cells, whereas overexpressed Trip10 substantially suppressed colony formation in CP70 cells and tumorigene sis in mice inoculated with CP70 cells. Conclusions: Trip10 regulates cancer cell growth and death in a cancer type-specific manner. Differential DNA methylation of Trip10 can either promo te cell survival or cell death in a cell type-dependent manner. Background Trip10 is a sc affold protein with F-BAR, ERM, and SH3 domains. Because these domains interact with diverse signaling partners, Trip10 is involved in various cellular processes including insulin-stimulated glucose uptake, endocytosis, cytoskeleton arrangement, membrane invagi- nation, proliferation, survival, and migration, in a tissue- specific and cell lineage-specific manner. In adipocytes, Trip10 increases glucose uptake by interacting with TC- 10 to regulate insulin-stimulated glucose transporter 4 (Glut4) translocation to the plasma membrane [1,2]. However, in muscle cells, Trip10 inhibits glucose uptake by increasing Glut4 endocytosis [3,4]. In natural killer cells, Trip10 regulates actin cytoskeleton dynamics by interacting with WASP protein [5,6], and regulates cyto- toxicity by facilitating localization of microtubule organiz- ing centers to immunological synapses [7]. Trip10 is also a regulator or modulator of cell survival after DNA damage [8] and in the human brain affected by Hunting- ton’s disease [9]. Trip10 expression is decreased in hepa- tocyte growth factor/scatter factor (HGF/SF)-mediated cell protection against DNA damage, but is significantly increased during hyperbaric oxygen-induced neuroprotec- tion [10]. On the other hand, overexpression of Trip10 was observed in human Huntington’s disease brain stria- tum, and neuronal Trip10 immunoreactivity increased with neuropathological severity in the neostriatum of * Correspondence: bioshh@ccu.edu.tw † Contributed equally 1 Human Epigenomics Center, Department of Life Science, Institute of Molecular Biology and Institute of Biomedical Science, National Chung Cheng University, Chia-Yi, Taiwan Full list of author information is available at the end of the article Hsu et al. Journal of Biomedical Science RESEARCH ARTIC LE Open Access Transcriptional analysis of cell growth and morphogenesis in the unicellular green alga Micrasterias (Streptophyta), with emphasis on the role of expansin Katrijn Vannerum 1,2,3 , Marie JJ Huysman 1,2,3 , Riet De Rycke 2,3 , Marnik Vuylsteke 2,3 , Frederik Leliaert 4 , Jacob Pollier 2,3 , Ursula Lütz-Meindl 5 , Jeroen Gillard 1,2,3 , Lieven De Veylder 2,3 , Alain Goossens 2,3 , Dirk Inzé 2,3 and Wim Vyverman 1* Abstract Background: Streptophyte green algae share several characteristics of cell growth and cell wall formation with their relatives, the embryophytic land plants. The multilobed cell wall of Micrasterias denticulata that rebuilds symmetrically after cell division and consists of pectin and cellulose, makes this unicellular streptophyte alga an interesting model system to study the molecular controls on cell shape and cell wall formation in green plants. Results: Genome-wide transcript expression profiling of synchronously growing cells identified 107 genes of which the expre ssion correlated with the growth phase. Four transcripts showed high similarity to expansins that had not been examined previously in green algae. Phylogenetic analysis suggests that these genes are most closely related to the plant EXPANSIN A family, although their domain organization is very divergent. A GFP-tagged version of the expansin-resembling protein MdEXP2 localized to the cell wall and in Golgi-derived vesicles. Overexpression phenotypes ranged from lobe elongation to loss of growth polarity and planarity. These results indicate that MdEXP2 can alter the cell wall structure and, thus, might have a function related to that of land plant expansins during cell morphogenesis. Conclusions: Our study demonstrates the potential of M. denticulata as a unicellular model system, in which cell growth mechanisms have been discovered similar to those in land plants. Additionally, evidence is provided that the evolutionary origins of many cell wall components and regulatory genes in embryophytes preced e the colonization of land. Background Although the form and function of plant cells are strongly correlated, the processes that determine the cell shape remain largely unknown. Plant cell morphogenesis is regulated in a non-cell-autonomous fashion by the surrounding tissues [1], hormone interference during ontogenesis, and sometimes by polyploidy as a conse- quence of endoreduplication [2,3]. In contrast, in unicel- lular relatives of land plants, it is possible to study the endogenous controls of cell morphogenesis without the interference by interacting cells and to better understand how these mechanisms ha ve evolved in the green lineage. The desmid Micrasterias denticulata is a member of the conjugating green algae (Zygnematophyceae) that comprise the closest extant unicellular relatives of land plants [4-8]. M. denticulata cells consist of two bilater- ally symmetrical flat semicells, notched deeply around their perimeter into one polar lobe and four main lateral lobes. Following cell division, each semicell builds a new one th rough a process of septum bulging and symmetri- cal local growth cessations to form the successive lobes (Figure 1A). After completion of the primary wall (dur- ing the doublet stage), a rigid cellulosic secondary cell wall pierced by pores is deposited, followed by shedding of it. This p eculiar grow th mechanism makes * Correspondence: Wim.Vyverman@UGent.be 1 Laboratory of Protistology and Aquatic Ecology, Department of Biology, Ghent University, 9000 Gent, Belgium Full list of author information is available at the end of the article Vannerum et al. BMC Plant Biology 2011, 11:128 http://www.biomedcentral.com/1471-2229/11/128 © 2011 Vannerum et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in STUDY OF HUMAN NASAL EPITHELIAL STEM OR PROGENITOR CELL GROWTH AND DIFFERENTIATION IN AN in vitro SYSTEM LI YINGYING (Master of Medicine, Wuhan University, P.R. China) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF OTOLARYNGOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2014 i Declaration I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously Li Yingying Aug 2014 ii Acknowledgement First and foremost I want to thank my supervisor, Assoc. Prof. Wang De Yun. It has been an honor to be his PhD student. He has taught me not only knowledge, but also the philosophy of life. I still remember the scene that he asked me to spell the full name of PhD and showed me how to understand the meaning of PhD when we first met. During these four years, the joy and enthusiasm he has for his research was contagious and motivational for me. I am also thankful for the excellent example he has provided as a successful scientist and professor. The members of the ENT research lab have contributed immensely to my personal and professional time at NUS. This group has been a source of friendships as well as good advice and collaboration. I am especially grateful for my senior, Dr. Li Chun Wei. He helped me be familiar to many of research works with great patience and selflessly shared with me some tips he picked up during his experience. I would like to acknowledge the senior research fellow, Dr. Yu Feng Gang. I very much appreciated his enthusiasm, intensity, willingness to share his knowledge on stem cell culture and inspired me with amazing ideas. In addition, I would also thank other members in this lab: Ms. Liu Jing, Dr. Yan Yan and Dr. Louise Tan Soo Yee. Without their generous help and support, I could not fulfill my PhD work. I must specially thank Assoc. Prof. Thomas Loh, our head of department, who gives me a help and support in my study. I would also like to appreciate the help from all the doctors in our department, especially Assoc. Prof. Chao Siew Shuen, iii who gives us a great support with clinic samples supply. I need to thank the sharing of clinic ideas from Dr. Lim Chwee Ming and Dr. Ng Chew Lip. Throughout my PhD study, we have many collaboration works with exchangestudents from China and I have had the pleasure moment to work with them. The optimization of components and description of characteristics for hNESPCs was mainly finished by Dr. Zhao Xue Ning from Shandong University (Shandong, China). The differentiation study was also collaborated with her. For comparison study for hNESPCs from NP and healthy controls, Dr. Yu Xue Ming from Shandong University (Shandong, China) helped me to trace the proliferation of progenitor cell. In my later work of cilia impairment in hyperplasia epithelium in NP, Dr. Gao Tian from Haerbin medical University (Heilongjiang, China), Dr. Jin Peng and Dr. Duan Chen from Shandong University (Shandong, China) help me a lot in staining works. Other peoples, who are not our major collaborators, also have given me a great help in my work for these years. My lab neighbors, Ms. Wen Hong Mei, Dr. Huang Chiung Hui, Dr. Kuo I-Chun, and Dr. Seow See Voon from Department of Pediatrics always give me assistance and let me share the facilities with them. Ms. Li Chun Mei from Department of Anaesthesia always lent me a hand with my routine lab work. I should like to express my gratitude for your kindness iv I also thank National University of Singapore for giving me the chance to pursue PhD and offering me the scholarship. And last but not least, this dissertation is dedicated to my family. My parents are always standing with me and giving me endless love and encouragement. My husband is always showing his patience and thoughtfulness to my work, and teaching me .. .Cell Growth and Division Cell Cycle The two major phases of the cell cycle include mitosis (cell division) , and interphase, when the cell grows and performs all of its... in larger cells with more than one nucleus Usually this is an unwanted aberration and can be a sign of cancerous cells 5/10 Cell Growth and Division Cell Cycle Control A very elaborate and precise... interphase ([link]) and in the following order: prophase, metaphase, anaphase, and telophase The process is then followed by cytokinesis 3/10 Cell Growth and Division Cell Division: Mitosis Followed