Genetic determinants of response to chemotherapy in transgenic mouse mammary and salivary tumors

• Published in: Oncogene Vol. 19; no. 8; pp. 1114 - 1122
• Main Authors: Bearss, D J, Subler, M A, Hundley, J E, Troyer, D A, Salinas, R A, Windle, J J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 21-02-2000
• Subjects: Animal models; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Breast cancer; Cancer; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell death; Cell Division - drug effects; Cell Division - genetics; Chemotherapy; DNA damage; Doxorubicin; Doxorubicin - pharmacology; Drug therapy; Female; Genes; Genes, ras; Genetic aspects; Genotypes; Growth factors; Health aspects; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - genetics; Mammary Tumor Virus, Mouse - genetics; Mice; Mice, Inbred Strains; Mice, Transgenic; mouse mammary tumor virus; Myc protein; Oral cancer; p53 Protein; Paclitaxel; Paclitaxel - pharmacology; Physiological aspects; S phase; Salivary Gland Neoplasms - drug therapy; Salivary Gland Neoplasms - genetics; Salivary gland tumors; Transgenic animals; Transgenic mice; Tumor Suppressor Protein p53 - genetics; Tumors; United States; United States > US; Texas
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1203275

Several transgenic mouse tumor models were utilized to explore how specific genetic alterations affect the tumor cell response to chemotherapeutic agents in vivo. Specifically, MMTV-ras transgenic mice were interbred to p53 knock-out mice to create a model for assessing the role of p53 in chemotherapeutic responses. In addition, MMTV-ras tumors were compared to MMTV-myc and MMTV-ras/myc tumors. Mice of each genotype reproducibly develop mammary and/or salivary tumors, but tumor growth dynamics vary considerably between genotypes. MMTV-ras/p53-/- tumors exhibit higher S phase fractions than MMTV-ras/p53+/+ tumors, although both tumor types display very low apoptosis levels. In contrast, MMTV-myc tumors exhibit both high S phase fractions and spontaneous apoptosis levels. Tumor-bearing mice of each genotype were treated with either doxorubicin or paclitaxel, and effects on overall tumor growth, cell cycle distribution and apoptosis were evaluated. Surprisingly, neither agent efficiently induced apoptosis in any of the tumor models, including those with wildtype p53. Rather, tumor responses were mediated primarily by changes in cell cycle distribution. However, the spontaneous apoptosis levels did serve as a predictor of tumor growth response, in that only those tumors with high pretreatment apoptosis levels underwent significant regression following treatment with either agent.