Amundadottir L T, Johnson M D, Merlino G, Smith G H, Dickson R B
Vincent T. Lombardi Cancer Research Center, Georgetown University, Washington, DC 20007, USA.
Cell Growth Differ. 1995 Jun;6(6):737-48.
The c-myc oncogene is commonly amplified in breast cancer and is known to interact synergistically with transforming growth factor alpha (TGF alpha) in vitro to promote phenotypic transformation of mammary epithelial cells. In addition, both genes are under sex steroid hormone regulation in breast cancer. We have used a bitransgenic mouse approach to test the relevance of Myc-TGF alpha interaction in mammary gland tumorigenesis of virgin animals in vivo. We mated single transgenic TGF alpha and c-myc mouse strains to yield double transgenic offspring for TGF alpha and c-myc. All (20 of 20) double transgenic TGF alpha/c-myc animals developed synchronous mammary tumors at a mean age of 66 days. An unexpected finding was that tumor latency and frequency in males and virgin females were identical. Thus, two gene products that are known to be coinduced in breast cancer by the sex hormones estrogen and progesterone strongly synergize to induce synchronous mammary tumors, independent of sex. The tumors, despite being estrogen receptor positive, were readily transplanted as highly malignant s.c. cancers in ovariectomized nude mice. Although approximately one-half of single transgenic c-myc virgin females also eventually developed mammary gland tumors, these were stochastic and arose after a long latency period of 9-12 months. Single transgenic virgin TGF alpha females and males, c-myc males, and transgene-negative littermates did not develop tumors (ages up to 15 months). The salivary glands of double transgenic animals also coexpress the two transgenes and show pathological abnormalities ranging from hyperplasias to frank adenocarcinomas. In contrast, the salivary glands of single transgenic and wild-type animals showed only mild hyperplasias or metaplasias, but tumors were not observed. In situ hybridization analysis of mammary and salivary glands revealed that hyperplastic and tumorous areas colocalize with regions that overexpress both the TGF alpha and c-myc transgenes. This indicates that there is a requirement for the presence of both proteins for transformation of these glands. In summary, TGF alpha and c-Myc synergize in an extremely powerful way to cause breast and salivary gland tumorigenesis in males and virgin females without a requirement for pregnancies.
c-myc癌基因在乳腺癌中通常会扩增，并且已知在体外它能与转化生长因子α（TGFα）协同作用，促进乳腺上皮细胞的表型转化。此外，在乳腺癌中这两个基因都受性类固醇激素调控。我们采用双转基因小鼠方法来测试Myc-TGFα相互作用在未生育动物乳腺肿瘤发生中的相关性。我们将单转基因TGFα和c-myc小鼠品系进行交配，以产生TGFα和c-myc的双转基因后代。所有（20只中的20只）双转基因TGFα/c-myc动物在平均66日龄时都同步发生了乳腺肿瘤。一个意外的发现是，雄性和未生育雌性的肿瘤潜伏期和发生率是相同的。因此，已知在乳腺癌中由性激素雌激素和孕激素共同诱导的两种基因产物强烈协同作用，诱导同步乳腺肿瘤，与性别无关。这些肿瘤尽管雌激素受体呈阳性，但很容易作为高度恶性的皮下癌移植到去卵巢的裸鼠体内。虽然大约一半的单转基因c-myc未生育雌性最终也发生了乳腺肿瘤，但这些肿瘤是随机发生的，且在9至12个月的长潜伏期后才出现。单转基因未生育TGFα雌性和雄性、c-myc雄性以及转基因阴性同窝小鼠未发生肿瘤（年龄达15个月）。双转基因动物的唾液腺也共同表达这两个转基因，并表现出从增生到明显腺癌的病理异常。相比之下，单转基因和野生型动物的唾液腺仅表现出轻度增生或化生，但未观察到肿瘤。对乳腺和唾液腺的原位杂交分析表明，增生和肿瘤区域与同时过度表达TGFα和c-myc转基因的区域共定位。这表明这两种蛋白质的存在对于这些腺体的转化是必需的。总之，TGFα和c-Myc以极其强大的方式协同作用，导致雄性和未生育雌性发生乳腺和唾液腺肿瘤，而无需怀孕。
