Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice: reduction in protective apoptotic response at the preneoplastic stage

The dramatic increase in apoptosis observed during the development of preneoplastic mammary lesions is associated with a significant elevation in Bar expression in C3(1)/SV40 large T antigen (TAg) transgenic mice. The significance of Bar expression during tumor progression ill vivo was studied by generating double-transgenic mice carrying the C3(1)/TAg transgene and mutant alleles for bax, C3(1)/TAg transgenic mice carrying mutant bax alleles exhibited accelerated rates of tumor growth, increased tumor numbers, larger tumor mass and decreased survival rates compared with mice carrying wild-type bax, Accelerated tumorigenesis associated with the bax(+/-) genotype did not require the loss of function of the second bar allele, Thus, haploid insufficiency of bar is enough to accelerate tumor progression, suggesting that the protective effect of Bar is dose-dependent. While levels of apoptosis in the preneoplastic lesions, but not carcinomas, were reduced in bax(+/-) or bax(-/-) mice compared with bax(+/+) mice, rates of cellular proliferation in mammary lesions were similar among all bar genotypes, These data demonstrate that bar is a critical suppressor of mammary tumor progression at the stage of preneoplastic mammary lesion development through the upregulation of apoptosis, but that this protective effect is lost during the transition from preneoplasia to invasive carcinoma. [References: 29]

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