Mester J, Wagenaar E, Sluyser M, Nusse R
J Virol. 1987 Apr;61(4):1073-8. doi: 10.1128/JVI.61.4.1073-1078.1987.
Mammary tumors in the GR mouse strain are caused by the expression of an endogenous provirus of the mouse mammary tumor virus (MMTV). The tumors progress from a hormone-dependent growth phase to autonomous, hormone-independent growth. We studied proviral insertion of MMTV at the int-1 and int-2 mammary oncogenes and the transcription of these genes during progression of a series of transplanted mammary tumors. During the hormone-dependent phase, 6 of 15 transplanted tumors were positive for proviral insertion at int-1 or int-2 or both. These tumors were oligoclonal with respect to the fraction of tumor cells with novel int-1 and int-2 restriction fragments and, apparently, consisted of different tumor cells with proviruses integrated at different oncogenes, including genes that are not yet known. In 10 tumors we detected expression of the int genes, indicating that most tumors contain minor populations of cells with int-1 or int-2 activations. On transplantation the tumors remained oligoclonal during the hormone-dependent phase. The hormone-independent variants of the tumors emerged as clonal outgrowths of cells with MMTV proviruses that could be traced back in the hormone-dependent tumors, but not always those of cells that were positive for insertions near int-1 or int-2. The maintenance of oligoclonality during the hormone-dependent phase suggests a growth-controlling effect of different populations of cells on each other. The clonal, hormone-independent tumors that arise later seem to be the result of mutations that are unrelated to int activation.
GR小鼠品系中的乳腺肿瘤是由小鼠乳腺肿瘤病毒（MMTV）的内源性前病毒表达引起的。肿瘤从激素依赖性生长阶段发展为自主性、激素非依赖性生长。我们研究了MMTV在前病毒插入int-1和int-2乳腺癌基因以及在一系列移植性乳腺肿瘤进展过程中这些基因的转录情况。在激素依赖性阶段，15个移植肿瘤中有6个在前病毒插入int-1或int-2或两者均为阳性。就具有新的int-1和int-2限制性片段的肿瘤细胞比例而言，这些肿瘤是寡克隆的，并且显然由不同的肿瘤细胞组成，这些肿瘤细胞的前病毒整合在不同的癌基因上，包括尚未知晓的基因。在10个肿瘤中我们检测到了int基因的表达，这表明大多数肿瘤含有少量具有int-1或int-2激活的细胞群体。在移植过程中，肿瘤在激素依赖性阶段保持寡克隆状态。肿瘤的激素非依赖性变体是作为具有MMTV前病毒的细胞的克隆性增殖出现的，这些细胞可以追溯到激素依赖性肿瘤中，但并非总是那些在int-1或int-2附近插入呈阳性的细胞。在激素依赖性阶段寡克隆性的维持表明不同细胞群体之间存在生长控制作用。后来出现的克隆性、激素非依赖性肿瘤似乎是与int激活无关的突变的结果。
