Mammary Gland Cancer Models(updated 10/15/03)
Eva Y.-H. P. Lee1, Lalage Wakefield2, Maria J. Merino3, Gertraud Robinson4 Aihua Li1, Philip Carpenter5 Wen-Hwa Lee1, Robert Cardiff6,
and Jeffrey E. Green7
1Dept of Developmental & Cell Biology and
Dept. of Biological Chemistry -
University of California, Irvine, CA
2Laboratory of Cell Regulation and Carcinogenesis -
National Cancer Institute Bethesda, MD
3Laboratory of Pathology - National Cancer Institute
Bethesda, MD
4Laboratory of Genetics and Physiology
National Institute of Diabetes and Digestive and Kidney Diseases
- National Institutes of Health Bethesda, MD
5Dept. of Pathology -
University of California, Irvine, CA
6Center for Comparative Medicine
98 County Road and Hutchison Drive -
University of California, Davis, CA
7Transgenic Oncogenesis Group
Laboratory of Cell Regulation and Oncogenesis -
National Institute of Health Bethesda, MD
Welcome to the MMHCC Breast Cancer Site. On this web site, you will find a brief
introduction to breast cancer, including cancer incidence, diagnosis, treatment,
disease etiology, and modeling of the disease. The introductory section is followed by
several sections with more detailed information and discussion of specific topics listed below:
Introduction
Eva Lee
Dept of Developmental & Cell Biology and Dept. of Biological Chemistry, University of California, Irvine, CA
Breast cancer is the most commonly diagnosed form of cancer and the second leading cause of cancer
deaths in western women. One out of 8 to 10 women will develop breast cancer during her lifetime.
It is estimated that there are approximately 203,500 new cases in the year 2002 in the U.S. alone
(Jemal et al., 2002). Among all diagnosed breast cancers, male breast carcinoma accounts for 1% of the
cases. Advances have been made in breast cancer diagnosis, therapy and prevention. Significant progress in understanding of
underlying genetic changes that contribute to the formation and progression of breast cancer have been made.
Human breast cancer arises from normal cells through the accumulation of multiple
mutations, including loss-of-function mutations of tumor suppressor genes and
activational mutations of oncogenes. Epigenetic changes, i.e. silencing of genes through promoter
hypermethylationhas also been reported (reviewed in Widschwendter and Jones, 2002) Identification
of tumor suppressor genes has been
facilitated by the study of familial breast cancer. Approximately 10% of all breast
cancer cases can be linked to heritable transmission of an autosomal dominant allele.
Fifteen to twenty percent of these familial breast cancers can be accounted for by
germ-line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2. Rare
germ-line mutations in p53 and CHK2 (Li-Fraumeni syndrome), PTEN (Cowden syndrome) and
the serine threonine kinase STK11/LKB1 (Peutz-Jegher syndrome) account for another small
fraction of the familial cases (Nathanson et al., 2001). Genes for the remaining familial
clusters are unknown and may be caused by low-penetrance susceptibility genes. Causes for sporadic cancers are not clear, but many genes that contribute
to growth and apoptosis have been found deregulated in sporadic breast cancer.
Mammography has long been the major technique for the screening of breast
cancer. The US National Institute of Health recommends regular mammograms for women over
40, but there are debates regarding the effectiveness of this screening method
(Nature, 415: 950, 2002). There are also emerging techniques for improved sensitivity of
breast cancer imaging. For example, with the introduction of contrast agents and other
advancements, magnetic resonance imaging (MRI) has the potential to become a useful
adjuvant in breast imaging with the promise for detection, diagnosis, and staging of breast
cancer (Orel and Schnall, 2001). But issues, including cost-effectiveness and
standardized data interpretation, etc., have hampered its usage in clinical
practice.
Early detection of breast cancer and optimal combination of surgery, chemotherapy,
hormone therapy, and radiation therapy result in a decrease of local recurrence or
development of metastatic cancer, contributing to the reduction of deaths by more than
50% (Hortobagyi, 2000). However, there is currently no effective cure for metastatic
breast cancer.
The development of breast cancer models has provided important insights into breast
tumor biology, and has facilitated the development and testing of novel therapeutic
approaches for breast cancer. Spontaneous, chemical carcinogen-induced, or genetically
modified mice are widely used as model systems. Carcinogen-induced mammary tumors in
rats have also been extensively studied. There have been significant improvements in
the technology of modeling human breast cancer in mice since the first transgenic mouse
with mammary tumors was reported by Stewart et al. in 1984 (Stewart et al., 1984).
Mouse strains harboring knockout of tumor suppressor genes, and mice strains carrying
conditional alleles of oncogenes and tumor suppressor genes have been generated. The
improvement has resulted in models that more accurately mimic the human situation in
which genetic alterations occur in a subset of somatic cells. Some mouse models have
been used in cancer prevention and cancer therapeutic studies. Importantly, mouse models
have allowed the investigation of distinct pathways involved in breast cancer. These
animal models are valuable for target validation in cancer drug discovery and may help
alleviate the bottleneck in the drug discovery process.
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