Conditional mouse models demonstrate oncogene-dependent differences in tumor maintenance and recurrence.

Maddalena T Tilli,Priscilla A Furth

doi:10.1186/bcr614

Abstract

Diversity in the pathophysiology of breast cancer frustrates therapeutic progress. We need to understand how mechanisms activated by specific combinations of oncogenes, tumor suppressors, and hormonal signaling pathways govern response to therapy and prognosis. A recent series of investigations conducted by Chodosh and colleagues offers new insights into the similarities and differences between specific oncogenic pathways. Expression of three oncogenes relevant to pathways activated in human breast cancers (c-myc, activated neu and Wnt1) were targeted to murine mammary epithelial cells using the same transgenic tetracycline-responsive conditional gene expression system. While the individual transgenic lines demonstrate similarly high rates of tumor penetrance, rates of oncogene-independent tumor maintenance and recurrence following initial regression are significantly different, and are modifiable by mutations in specific cooperating oncogenes or loss of tumor suppressor gene expression. The experiments make three notable contributions. First, they illustrate that rates of tumor regression and recurrence following initial regression are dependent upon the pathways activated by the initiating oncogene. The experiments also demonstrate that altered expression or mutation of specific cooperating oncogenes or tumor suppressor genes results in different rates of tumor regression and recurrence. Finally, they exemplify the power of conditional mouse models for elucidating how specific molecular mechanisms give rise to the complexity of human cancer.

Highlights

Conditional transgenic mouse models expressing oncogenes involved in human cancer pathways have revolutionized the way in which we define the contributions that these oncogenes lend to the process of tumorigenesis
Adaptation of the tetracycline-responsive gene expression system to transgenic mice [6,7,8,9] prepared the way for development of conditional models in which precise timing of oncogene exposure in specific tissues initiated events that model those that occur during the stepwise progression of human oncogenesis [10,11,12,13,14,15,16,17,18]
Oncogenic pathways can be examined in individual tissues and cancer systems to determine whether there will be oncogene-independent growth, and if so to which alternative pathways the cells turn in order to bypass oncogene dependence

Summary

Introduction

Seventy-eight percent of mammary adenocarcinomas without ras mutation regress, while adenocarcinomas with ras mutation do not regress after c-myc downregulation In these experiments neoplastic reversal is due either to rapid apoptosis of tumor cells [12,13,14,16] or to redifferentiation of cells causing arrest of proliferation and loss of malignant potential [16]. Transgenic mice with conditional expression of activated Neu in mammary epithelial cells were designed (MTB/TAN mice) to examine the dependence of continued oncogene expression on activated Neu-initiated tumors and metastases [19]. Chodosh and colleagues used the same conditional system to examine the requirement of continued Wnt expression in the maintenance and recurrence of mammary cancers by developing double transgenic mice with conditional expression of Wnt (MTB/TWNT mice) [21]. Even though p53 is not required for regression of Wnt1induced tumors, 40% of the tumors that develop in p53 heterozygous mice do not regress when Wnt is downregulated, and a high percentage (76%) of the adenocarcinomas that do regress subsequently recur

Conclusion

Findings

Trosko JE