Abstract

A cardinal feature of human cancers is the progressive selection and outgrowth of cells that possess increasingly aggressive properties. This process ultimately leads to resistance to therapeutic agents, distant metastasis, and tumor recurrence. Together, these three manifestations of tumor progression are responsible for the vast majority of cancer deaths. Nevertheless, while tumor progression constitutes a problem of unrivaled clinical importance, the mechanisms underlying it are largely unknown. As such, elucidating the molecular, cellular, and pathophysiological events that contribute to tumor progression is a critical priority in cancer research. To better define the genetic, cellular, molecular, and physiological events that contribute to breast cancer progression, we have created a series of novel inducible bitransgenic mouse models in which the oncogenes c-myc, Neu, Wnt1, v-Ha-Ras, and Akt1 can be conditionally expressed in the mammary epithelia of animals treated with tetracycline derivatives. Tumor formation in each of these models is highly penetrant, mammary-specific, and absolutely dependent on transgene induction by doxycycline. The properties of this model system permit the direct visualization and analysis of each stage of mammary tumorigenesis from normal mammary tissue in the uninduced state to hyperplasias, atypical hyperplasias, invasive carcinomas, and distant metastases that arise as a consequence of oncogene activation. The inducible nature of the transgenic models that we have developed permits essentially complete downregulation of an oncogenic stimulus within an intact tumor. Remarkably, we have found that–following transgene deinduction by doxycycline withdrawal–many of these oncogene-induced primary mammary tumors rapidly regress to a clinically undetectable state. However, despite this dramatic regression behavior, a substantial fraction of tumors that have previously regressed to a non-palpable state recur spontaneously in the absence of transgene expression over periods of up to 1 year. This finding suggests that many animals in whom tumors have regressed still harbor residual cancerous disease and that additional genetic events may occur in these remaining cells that lead to the recurrence of actively growing tumors. In addition, we have further demonstrated that a subset of primary mammary tumors fail to regress fully following doxycycline withdrawal, and instead acquire the ability to survive and grow in the absence of oncogene overexpression. In some cases, this behavior is associated with identifiable spontaneous genetic events that are tightly linked to the ability of tumors to progress to transgene independence. In aggregate, the tendency of mammary tumors in this system to metastasize, to develop resistance to oncogene downregulation, and to recur spontaneously with long latency suggests that these models mimic critical aspects of the natural history of human breast cancer. As such, this system may represent a valuable new means to understand the biology of tumor progression and to identify the molecular mechanisms by which mammary tumors escape their dependence on particular oncogenic pathways for growth.

Highlights

  • The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer

  • We report that somatic mutations of p53 in mouse mammary epithelial cells lead to ERα-positive and ERαnegative tumors. p53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells

  • Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors

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Summary

Mouse models of human breast cancer: evolution or convolution?

Transgenic Oncogenesis Group, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland, USA. The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer. The relationships of these models to human breast cancer, remain problematic. P53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells. These tumors have a high rate of metastasis that is independent of tumor latency. Since it is feasible to isolate ERα-positive epithelial cells from normal mammary glands and tumors, molecular mechanisms underlying ERα-positive and ERα-negative mammary carcinogenesis can be systematically addressed using this model

Mouse models for BRCA1-associated breast cancer
Genetic manipulation of the mammary gland by transplantation
The Mutant Mouse Regional Resource Center Program
11 Mammary pathology of the genetically engineered mouse
D Dugger
15 Role of animal models in oncology drug discovery
18 Clinical breast cancer and estrogen
19 Pregnancy levels of estrogen prevents breast cancer
21 The ErbB receptor tyrosine kinases and their roles in cancer
22 Predicting breast cancer behavior by microarray analysis
24 The comparative genetics and genomics of cancer: of mice and men
23 The molecular biology of mammary intraepithelial neoplasia outgrowths
28 Transgenic models are predictive: the herceptin and flavopiridol experience
31 Role of differentiation in carcinogenesis and cancer prevention
30 Genetically engineered mouse models of human breast cancer
34 Hormonal interactions during mammary gland development
35 Function of LEF1 in early mammary development
40 Imaging mouse models of breast cancer with positron emission tomography
42 Ultrasound imaging of tumor perfusion
D Medina
47 In situ to invasive carcinoma transition: escape or release
48 Regulation of human mammary stem cells
50 Stem cells in normal breast development and breast cancer
McKenzie
57 Genomic approaches to drug target discovery using mouse models
58 Target discovery in the postgenomic era
60 From gene expression patterns to antibody diagnostics
Findings
A Korman
Full Text
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