Kuperwasser C, Hurlbut G D, Kittrell F S, Dickinson E S, Laucirica R, Medina D, Naber S P, Jerry D J
Program in Molecular and Cellular Biology, Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts, USA.
Am J Pathol. 2000 Dec;157(6):2151-9. doi: 10.1016/S0002-9440(10)64853-5.
Breast cancer is the most frequent tumor type among women in the United States and in individuals with Li-Fraumeni syndrome. The p53 tumor suppressor gene is altered in a large proportion of both spontaneous breast malignancies and Li-Fraumeni breast cancers. This suggests that loss of p53 can accelerate breast tumorigenesis, yet p53-deficient mice rarely develop mammary tumors. To evaluate the effect of p53 loss on mammary tumor formation, the p53(null) allele was back-crossed onto the BALB/c genetic background. Median survival was 15.4 weeks for BALB/c-p53(-/-) mice compared to 54 weeks for BALB/c-p53(+/-) mice. Sarcomas and lymphomas were the most frequent tumor types in BALB/c-p53(-/-) mice, whereas 55% of the female BALB/c-p53(+/-) mice developed mammary carcinomas. The mammary tumors were highly aneuploid, frequently lost the remaining wild-type p53 allele, but rarely lost BRCA1. Although mammary tumors were rarely detected in BALB/c-p53(-/-) female mice, when glands from BALB/c-p53(-/-) mice were transplanted into wild-type BALB/c hosts, 75% developed mammary tumors. The high rate of mammary tumor development in the BALB/c background, but not C57Bl/6 or 129/Sv, suggests a genetic predisposition toward mammary tumorigenesis. Therefore, the BALB/c-p53(+/-) mice provide a unique model for the study of breast cancer in Li-Fraumeni syndrome. These results demonstrate the critical role that the p53 tumor suppressor gene plays in preventing tumorigenesis in the mammary gland.
乳腺癌是美国女性以及李-弗劳梅尼综合征患者中最常见的肿瘤类型。在大部分自发性乳腺恶性肿瘤和李-弗劳梅尼综合征相关性乳腺癌中，p53肿瘤抑制基因都发生了改变。这表明p53功能缺失可加速乳腺肿瘤发生，然而p53基因缺陷型小鼠很少发生乳腺肿瘤。为了评估p53缺失对乳腺肿瘤形成的影响，将p53（无效）等位基因回交到BALB/c遗传背景。BALB/c-p53（-/-）小鼠的中位生存期为15.4周，而BALB/c-p53（+/-）小鼠为54周。肉瘤和淋巴瘤是BALB/c-p53（-/-）小鼠中最常见的肿瘤类型，而55%的雌性BALB/c-p53（+/-）小鼠发生了乳腺癌。乳腺肿瘤高度非整倍体，经常丢失剩余的野生型p53等位基因，但很少丢失BRCA1。尽管在BALB/c-p53（-/-）雌性小鼠中很少检测到乳腺肿瘤，但当将BALB/c-p53（-/-）小鼠的乳腺腺体移植到野生型BALB/c宿主中时，75%的宿主发生了乳腺肿瘤。在BALB/c背景下乳腺肿瘤的高发生率，而不是在C57Bl/6或129/Sv背景下，提示存在乳腺肿瘤发生的遗传易感性。因此，BALB/c-p53（+/-）小鼠为研究李-弗劳梅尼综合征中的乳腺癌提供了一个独特的模型。这些结果证明了p53肿瘤抑制基因在预防乳腺肿瘤发生中所起的关键作用。
