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

Abstract

Several transgenic mouse tumor models were utilized to explore how speci®c genetic alterations aect the tumor cell response to chemotherapeutic agents in vivo. Speci®cally, 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 7/7 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 eects on overall tumor growth, cell cycle distribution and apoptosis were evaluated. Surprisingly, neither agent eciently 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 signi®cant regression following treatment with either agent.

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

“…Thus, in our leukemia model downregulation of p21 WAF1 by c-Myc does not switch the p53 activity from cytostatic to proapoptotic, as has been found in colon cancer cells (Seoane et al, 2002). Our results are in agreement with the lack of effect of p21 WAF1 on Myc-induced apoptosis of mammary cells in vivo (Bearss et al, 2002). As BAX is a proapoptotic protein induced by p53, a defective upregulation of BAX in cells expressing c-Myc could explain the apoptosis reduction.…”

Telomeres and telomerase in hematologic neoplasia

“…These and other might also shed some light on their e ects on anti-telomerase therapy for hematologic neoplasias (Bearss et al, 2000). For example, Tauchi et al (unpublished data) have demonstrated that inhibition of telomerase using a dominant negative (DN)-hTERT expression vector in BCR/ABL-transformed cells leads to progressive telomere shortening and apoptosis.…”

Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice

“…The role of these proteins in facilitating tumor formation and development has also been demonstrated in combination with other genetic alterations. Thus, the absence of p21 accelerates the development of some tumors, such us pituitary tumors in Rb-haploinsufficient mice and in INK4c-null mice (Brugarolas et al, 1998;Franklin et al, 2000), breast tumors in Ras transgenic mice (Adnane et al, 2000;Bearss et al, 2002) and intestinal tumors in Apc-haploinsufficient mice (Yang et al, 2001). In contrast, the absence of p21 has no effect on the tumor-prone phenotype of mice deficient for the Werner syndrome gene (Lebel et al, 2001), nor in Myc-induced lymphomas (Martins and Berns, 2002) and mammary tumors (Bearss et al, 2002).…”