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Contributions of Mouse Biology to Breast Cancer Research

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Contributions of Mouse Biology to Breast Cancer Research Comparative Medicine Vol 52, No 1 Copyright 2002 February 2002 by the American Association for Laboratory Animal Science Pages 12-31 Overview Contributions of Mouse Biology to Breast Cancer Research Table of Contents Introduction (R. D. Cardiff, M.D., Ph.D.) The University of California Origins of Experimental Breast Cancer Research: H. A. Bern, Ph.D. 1) The Mammary Gland-Free Fat Pad Transplantation Systems A) The Gland-Cleared Fat Pad: The Foundation for Mammary Immortality and Preneoplasia: L. J. Faulkin, Ph.D. B) Senescence of Mouse Mammary Epithelial Cells: C. W. Daniel, Ph.D. C) Mammary Epithelial Stem Cells: G. H. Smith, Ph.D. D) Preneoplasia: a. The Hyperplastic Outgrowth (HPO) in Mammary Tumor Biology: L. J. T. Young and D. Medina, P.h.D. b. The Mouse Mammary Tumor Virus and Mammary Tumorigenesis: R. D. Cardiff, M.D., Ph.D. c. Mammary Tumor Viruses in Wild Mice and Humans: M. B. Gardner, M.D. d. Comparative Pathology of the Mammary Gland: S. R. Wellings, M.D., Ph.D. 2) Hormonal Regulation A) Ovarian Hormones in Mammary Growth and Development: G. Shyamala, Ph.D. B) Preventing Breast Cancer with Estrogen: Mimicking the Protective Effect of Pregnancy: R. Guzman, Ph.D., L. Rajikumar, Ph.D., J. Yang, M.D., Ph.D., G. Thordarson Ph.D., and S. Nandi, Ph.D. 3) Genetically Engineered Mice and Neoplastic Progression A) Genetically Engineered Mice: R. D. Cardiff, M.D., Ph.D. B) Premalignancy a. The Preneoplastic Phenotype in the p53 Null Mammary Gland: D. Medina, Ph.D. b. PyV-mT: A New Model for Mammary Premalignancy: C. L. MacLeod, Ph.D. and L. J. T. Young C) Malignancy and Metastases a. The MMTV-LTR:PyV-mT Transgenic Mouse System and Metastasis: R. D. Cardiff, M.D., Ph.D. b. Genetic Modification of Tumors: An Ets2 Restriction of Mammary Tumors in Mice: R. G. Oshima, Ph.D., A. K. Man, L. J. T. Young and R. D. Cardiff, M.D. Ph.D. c. Signal Transduction and Metastatic Potential: E. T. Sawai, Ph.D. d. Mouse Models and Genomics: J. P. Gregg, M.D. e. Metastasis and Angiogenesis: A. T. W. Cheung, Ph.D. f. Application of Met-1 Transgenic Breast Cancer: Delineating Antiangiogenic Property of Paclitaxel (Taxol): L. J. T. Young and D. H. Lau, M.D., Ph.D. Summation (R. D. Cardiff, M.D., Ph.D.) Introduction breast cancer into a historical context, demonstrating the bio- Comparative medicine is based on the concept that animals logical basis for modern research. and humans often share the same disease. This concept is per- The symposium brought together many of the investigators haps best exemplified in mammary biology where the rodent who pioneered mammary cancer research for a day of scientific has been the primary animal model for human breast cancer. presentations and discussions with some of the current breast The following section reviews some of the key concepts in breast cancer researchers. The participants were all directly or indi- cancer research from the last five decades in the form of “epito- rectly connected to the “West Coast Mammary Biology Group,” mes” based on the second annual UC Davis Mouse Biology Pro- centered at the UC Berkeley Cancer Research Genetics Labora- gram Symposium, sponsored by the UC Davis Center for tory (CRGL), led by Drs. Kenneth B. DeOme and Howard A. Comparative Medicine. Taken together, these epitomes place Bern, and the event coincided with the 50th anniversary of the the current molecular, genomics and pre-clinical research in founding of the CRGL by DeOme. The assemblage also cel- 12 Mouse biology in breast cancer research ebrated the retirement of one of the participants, Lawrence J. T. Young, who had been involved in the key experiments through the five decades represented at the symposium. All participants submitted a summary of their symposium comments and of their research. The following sections are pre- sented in the “epitome” style; that is, short summaries of a field or concept. The first group of epitomes represents a historically significant review of the origin of many of the key concepts in mammary biology, frequently presented by the pioneering in- vestigators themselves. The concluding epitomes provide some specific examples of how current biological and pre-clinical re- search continues to be influenced by the earlier work. As indicated in the historical summary by Bern, the three ma- jor contributions of the CRGL under DeOme were in mammary preneoplasia, hormone regulation and the role of the mouse mammary tumor virus (MMTV) in mouse mammary tumorigen- esis. The development of the gland-cleared fat pad transplanta- tion techniques (Faulkin) led to operational definitions of senescence (Daniel), stem cells (Smith), and preneoplasia (Faulkin) in mouse mammary biology. Preneoplasia is a focal area of atypia with immortalized cells that are at high risk of undergoing malignant transformation. Senescence is the inabil- ity of a cell population to sustain growth on serial transplanta- tion. Stem cells are those cells in the population that are capable of regenerating the entire mammary gland. These concepts were expanded upon by many students, led by Medina, who developed the hyperplastic outgrowth (HPO) transplant lines that were used to characterize preneoplasia (Young and Medina). The concepts from the mouse mammary gland were applied Figure 1. Dr. Kenneth B. DeOme the founder of Cancer Research to the study of precancer in humans and became the basis for Genetics Laboratory at the University of California, Berkeley and current concepts of ductal carcinoma in situ (DCIS) (Wellings). leader of the West Coast Mammary Biology Group. Although operational proof by transplantation proved to be im- possible, Wellings and Jensen found that the human mammary gland has focal atypical lesions that are associated with breast engineered mice to focus on the hormone receptor rather than cancer. Their work is the foundation for the extensive studies of the hormone. This has permitted a more detailed molecular dis- Page, his colleagues, and others that have provided incontro- section of hormone regulation (Shyamala). However, the estro- vertible demographic evidence that the lesions identified by gen hormone is still a key factor in breast cancer. Rodent models Wellings are premalignant. Wellings and Cardiff have pointed are now being used to study how alteration in hormone balance out that the atypical lesions found in the mouse and the human may lead to early chemo-intervention, preventing breast cancer are in the terminal units of the breast (lobular) and are morpho- (Guzman and Nandi). logically identical. The symposium was designed to trace the background history The concepts and techniques developed in the 1960s are cur- of modern breast cancer research. These epitomes illustrate the rently being applied to genetically engineered mice (Medina, origins of the key concepts and how they are being applied in cur- MacLeod, Oshima, Sawai, Gregg, Cheung, and Lau) for detailed rent research. Each epitome is intended to stand on its own, with molecular analysis of genetic modifiers of cancer (Oshima), limited references to the key reviews and primary articles. The preneoplasia (Medina and MacLeod), metastases (Sawai and reader is invited to browse the epitomes to obtain an overview or Gregg), angiogenesis (Cheung) and therapeutic anti-angiogen- use the individual epitome as a source for further in-depth study. esis (Lau). Although current studies focus on the modern mo- Robert D. Cardiff lecular biology and molecular medicine, they are based on the University of California, Davis concepts of preneoplasia embodied in the hyperplastic alveolar nodule (HAN) and the hyperplastic outgrowth (HPO) and on The University of California Origins of the transplantation techniques developed by DeOme and his Experimental Breast Cancer Research students, Faulkin, Daniel and Medina. This symposium coincided with the 50th anniversary of the Another major CRGL contribution came in the area of hor- founding of the Cancer Research (Genetics) Laboratory (CR(G)L) mone regulation. This group was led by Howard Bern and his at the University of California, Berkeley, under the directorship student Satyabrata (Ranu) Nandi. They defined the hormones of Kenneth B. DeOme, professor of zoology (Fig. 1). The California regulating mouse mammary gland development (Shyamala). state legislature had provided funds to establish a colony of mice The CRGL group established the roles of estrogen, progester- of reliable genetic background to be made available to cancer one, prolactin and insulin in mammary gland growth and devel- researchers throughout the state and elsewhere. DeOme, a opment. Current investigators are now using genetically mammalian geneticist and comparative histopathologist, was 13 Vol 52, No 1 Comparative Medicine February 2002 the first director, who was followed by the tumor endocrinologist Satyabrata (Ranu) Nandi and now by the tumor molecular im- munologist James Allison. Since its inception, the primary focus of the laboratory was on experimental mammary cancer, and this remains a major domain of research to this day. DeOme attracted a variety of collaborators to the laboratory, including this author and Nandi as endocrinologists, Dorothy Pitelka and Morgan Harris as cell biologists, and David Weiss and Phyllis Blair as tumor immunologists. Accompanying these academic staff members were technicians, graduate and postdoctoral students (including MDs seeking the PhD degree and research careers), and visiting investigators. Many of the former predoctoral and postdoctoral students are now distin- guished professors in their own right, both in the U.S. and abroad. In the central program of the laboratory, devoted to under- standing the genesis and progression of mammary cancer, sig- Figure 2. Photomicrograph of a hematoxylin-stained whole mount nificant understanding was attained early on of the role of the from a MMTV-infected mouse mammary gland showing the classical sub-gross picture of a HAN. Note how it stands out from the sur- hyperplastic alveolar nodule (HAN) as a precancerous lesion, on rounding mammary gland.
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