Shibata M A, Liu M L, Knudson M C, Shibata E, Yoshidome K, Bandey T, Korsmeyer S J, Green J E
Laboratory of Cell Regulation and Carcinogenesis, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
EMBO J. 1999 May 17;18(10):2692-701. doi: 10.1093/emboj/18.10.2692.
The dramatic increase in apoptosis observed during the development of preneoplastic mammary lesions is associated with a significant elevation in Bax expression in C3(1)/SV40 large T antigen (TAg) transgenic mice. The significance of Bax expression during tumor progression in 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 bax allele. Thus, haploid insufficiency of bax is enough to accelerate tumor progression, suggesting that the protective effect of Bax 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 bax genotypes. These data demonstrate that bax 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.
在癌前乳腺病变发展过程中观察到的凋亡显著增加与C3(1)/SV40大T抗原（TAg）转基因小鼠中Bax表达的显著升高有关。通过构建携带C3(1)/TAg转基因和bax突变等位基因的双转基因小鼠，研究了体内肿瘤进展过程中Bax表达的意义。与携带野生型bax的小鼠相比，携带bax突变等位基因的C3(1)/TAg转基因小鼠表现出肿瘤生长速度加快、肿瘤数量增加、肿瘤体积增大和生存率降低。与bax+/-基因型相关的肿瘤发生加速并不需要第二个bax等位基因功能丧失。因此，bax的单倍体不足足以加速肿瘤进展，这表明Bax的保护作用是剂量依赖性的。虽然与bax+/+小鼠相比，bax+/-或bax-/-小鼠癌前病变中的凋亡水平降低，但癌组织中的凋亡水平未降低，且所有bax基因型的乳腺病变中细胞增殖率相似。这些数据表明，bax通过上调凋亡在癌前乳腺病变发展阶段是乳腺肿瘤进展的关键抑制因子，但在从癌前病变向浸润性癌转变过程中这种保护作用丧失。
