Role of differentiation in carcinogenesis and cancer prevention

Abstract

Breast Cancer Res 2003, 5(Suppl 1):1 (DOI 10.1186/bcr660) 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, however, remain problematic. Recent advances in genomic technologies offer significant opportunities to identify critical changes that occur during cancer evolution and to distinguish in a complex and comprehensive manner the key similarities and differences between mouse models and human cancer. Comparisons between mouse and human tumors are being performed using comparative genomic hybridization, gene expression profiling, and proteomic analyses. The appropriate use of genetically engineered mouse models of mammary cancer in preclin-ical studies remains an important challenge which may also be aided by genomic technologies. Genomic approaches to cancer are generating huge datasets that represent a complex system of underlying networks of genetic interactions. Mouse models offer a tremendous opportunity to identify such networks and how they relate to human cancer. The challenge of the future remains to decipher these networks in order to identify the genetic nodes of oncogenesis that may be important targets for chemoprevention and therapy. Breast Cancer Res 2003, 5(Suppl 1):2 (DOI 10.1186/bcr661) Approximately 70% of human breast cancers are estrogen receptor alpha (ERα)-positive, but the origins of ERα-positive and ERα-negative tumors remain unclear. Most mouse models produce only ERα-negative tumors. In addition, these mouse tumors metastasize at a low rate relative to human breast tumors. We report that somatic mutations of p53 in mouse mammary epithelial cells lead to ERα-positive and ERα-negative 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. These tumors have a high rate of metastasis that is independent of tumor latency. An inverse relationship between the number of targeted cells and median tumor latency was also observed. The median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for breast carcinogenesis. Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors. 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. Breast Cancer Res 2003, 5(Suppl 1):3 (DOI 10.1186/bcr662) Breast tumor suppressor gene 1 (BRCA1) is a well-known transcription regulator, mutations of which cause tumor formation in a tissue-specific manner. In the past years, we have studied functions of Brca1 in mouse models carrying a number of different mutations. We showed that impaired Brca1 function causes chromosome damages, failure of the G2/M cell cycle checkpoint, and centrosome amplification, leading to p53-dependent lethality. Our further analysis revealed that Brca1 also plays an important role in spindle checkpoint through regulating Mad2. We showed that mice carrying a targeted disruption of Brca1 in mammary epithelium developed mammary tumors at low frequency after long latency and the tumorigenesis was significantly accelerated in a p53 +/-genetic background. Mammary tumors were highly diverse in histopathology and displayed extensive genetic/molecular alterations , including overexpression of ErbB2, c-myc, p27 and cyclin D 1 , and downregulation of p16. The most noticeable change is expression of estrogen receptor alpha (ERα). We showed that the absence of Brca1 resulted in increased expression of ERα in epithelial cells at pre-malignant stages and initiating tumors. However, expression of ERα was diminished in tumors of more advanced stages. This observation suggests that ERα-mediated signals are involved in tumorigenesis. Finally, we provided evidence that BRCA1 affects the MAPK pathway through interacting with estrogen/ERα signals, which may account for tissue-specific tumorigenesis. These abstracts are online at http://breast-cancer-research.com/supplements/5/S1