Preface

Chapter 8 **MIG-6 and SPRY2 in the Regulation of Receptor Tyrosine Kinase Signaling: Balancing Act via Negative**

Yu-Wen Zhang and George F. Vande Woude

**Feedback Loops 199**

**VI** Contents

Losses of specific chromosomal regions are frequently reported in different human tumors, suggesting that these regions may contain important genes associated with tumor develop‐ ment. Cell fusion studies provided the first functional evidence for a class of negatively-act‐ ing tumor suppressor genes (TSGs) harbored on certain human chromosomes. Based on Knudson's "two-hit hypothesis", the first TSG, RB was identified. Since 1980s, many TSGs have been discovered by using different approaches. Accumulated knowledge indicates that TSGs not limited to tumor suppression play critical roles in various biological activities in human cells.

In 20132, InTech published a book called "Tumor Suppressor Genes", which covers the most important fields, from cell cycle control, signaling pathways, epigenetic regulation, and cur‐ rent challenges to therapeutic applications of known TSGs. Some well-studied TSGs, such as p53 and p16, and their regulatory mechanisms in tumor development are addressed in this book. However, TSG research is a fast growing area, and many novel approaches and find‐ ings have been discovered recently. Therefore, it is necessary to publish a new open access book that may provide future directions for TSG studies.

This book, "Future Aspects of Tumor Suppressor Genes", contains some important areas that were not mentioned in the previous book. The majority of known TSGs were identified from hereditary tumor syndromes. However, more than 90% of human tumors are sporadic cases, so it is always a challenge to identify tumor susceptibility loci in sporadic tumors. Using ani‐ mal models, authors in this book investigated whether strain-specific allele loss was an im‐ portant clue to identify tumor suppressors involved in tumor susceptibility, which should be interesting to many researchers. Other basic researches contain investigations of several TSG signaling pathways from different laboratories: START-GAP/DLC family proteins and their molecular pathways involved in the control of cell growth, E2F-mediated tumor suppressive mechanism associated with RB, p53, ARF, p27Kip1 and TAp73 transcription factors, and TSGs in the regulation of receptor tyrosine kinase signaling via a negative feedback loop. Understanding these signaling regulatory mechanisms may lead to findings of molecular tar‐ gets for cancer therapy. In recent years, it has been well-accepted that microRNAs are an abundant class of endogenous small RNA molecules that can regulate tumor development. To reflect the trends of these novel researches, authors in this book present an extensive re‐ view for current knowledge of microRNAs that play in the control of tumor growth and ther‐ apeutic application.

This book also includes some other fascinating fields and emerging subjects in TSG studies. For example, the application of Drosophila as a special model for tumor suppression studies is addressed, and future directions used for the pharmacological screening and therapy

strategies are also proposed. Natural compounds, such as polyphenols, interfere with the initiation and progression of cancer development via multiple TSG pathways. Recent evi‐ dence, demonstrating that these compounds are able to modulate various cellular activities, such as cell cycle arrest, anti-angiogenesis, and metastasis suppression, are summarized in the relevant chapter. Finally, the regulatory role of TSGs, such as p16, p53 and RB, in cell reprogramming, stemness transition process, and signaling networks of these genes during these cellular processes are extensively reviewed, which indicates that TSGs are actively in‐ volved in many aspects of stem cell biology and regenerative medicine.

I would like take this opportunity to express my gratitude to all authors and InTech staff for their contributions in this publication project, and I hope that this book will be helpful for students, researchers and clinicians.

> **Yue Cheng, PhD** Department of Clinical Oncology The University of Hong Kong

**Chapter 1**

**Strain-Specific Allele Loss: An Important Clue to**

Nobuko Mori and Yoshiki Okada

http://dx.doi.org/10.5772/55159

controls and prevention of cancers.

**1. Introduction**

Additional information is available at the end of the chapter

**Tumor Suppressors Involved in Tumor Susceptibility**

Development of tumors is controlled by multiple genes such as cellular oncogenes and tumor suppressors activated or inactivated by somatic mutations and/or epigenetic mechanisms. Tumor development is also controlled by heritable factors as well as environmental factors, i. e., diet, oxidative stress and sustained inflammation, as reviewed by a large number of recent reports [1-12]. Both heritable and environmental factors are important targets for clinical

Heritable factors underlying cancer risks have been identified in familial cancer-prone pedigrees. In the pedigree members, tumors develop in a Mendelian dominant inheritance fashion. Breast cancer 1, early onset (*BRCA1*) encoding a nuclear phosphoprotein that plays a role in maintaining genomic stability is one of the heritable cancer risk factors hitherto identified. Women bearing a mutated *BRCA1* allele are at high risk for both breast and ovarian cancers through their lifespan. According to the recent estimations, average cumulative risks in *BRCA1*-mutation carriers by age 70 years are 65% (95% confidence interval 44%–78%) for breast cancer and 39% (18%–54%) for ovarian cancer [13]. Thus, disease penetrance is incom‐ plete, albeit rather high, in the mutated-*BRCA1* carriers. The *BRCA1* gene maps to human chromosome 17q21, where frequent loss of heterozygosity (LOH) is observed in both familial and sporadic breast cancers. Although tumors developed in the *BRCA1*-mutation carriers are homozygous for the defective *BRCA1* allele via LOH mechanisms, sporadic cases rarely show mutation in the *BRCA1* gene [14]. The *BRCA1* gene may rather undergo inactivation via

Unlike the *BRCA1* case, tumor susceptibility is expressed in a non-Mendelian inheritance manner, because multiple genes with incomplete penetrance participate in the phenotype. Moreover, tumor susceptibility alleles may occasionally express genetic interaction, i. e.,

and reproduction in any medium, provided the original work is properly cited.

© 2013 Mori and Okada; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2013 Mori and Okada; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

epigenetic mechanisms such as DNA methylation in sporadic tumors.

**Chapter 1**
