The cell of origin of breast cancer metastasis

 描述（由申请人提供）：这项拟议研究的总体目标是探索癌症转移中非克隆进化的初步观察。乳腺癌是妇女最常诊断的癌症（皮肤癌除外），也是仅次于肺癌的第二大癌症死亡原因。乳腺癌起源于乳腺导管树的上皮细胞。我们以前已经开发了几个乳腺癌演变的体细胞小鼠模型，采用RCAS-TVA方法将癌基因引入体细胞组织。该模型还允许我们在体内完全发育的乳腺中遗传跟踪遭受初始致癌突变的少量乳腺上皮细胞。使用这种方法引入Wnt 1或ErbB 2以启动三阴性和HER 2乳腺癌亚型的形成，这两种最具聚集性的女性癌症亚型，我们发现了癌症非克隆进化的惊人证据。我们发现，在由此产生的乳腺肿瘤中，存在少量组织学上看起来像癌细胞的细胞，但令人惊讶的是，它们缺乏前病毒DNA和起始癌基因。此外，更出乎意料的是，我们发现肺中的许多转移灶也缺乏前病毒DNA及其致癌蛋白产物。这些意想不到的初步数据提出了一个挑衅性的假设，即随着最初突变的乳腺上皮细胞演变成癌症，邻近的正常乳腺上皮细胞没有遭受起始致癌突变，可以由突变细胞煽动成为癌性的，甚至转移性的。为了验证乳腺癌转移的非克隆假设，我们将追求三个目标：具体目标1：验证我们的初步小鼠模型发现，正常乳腺上皮细胞可以被相邻的癌基因激活的乳腺细胞刺激，进行肿瘤发生和转移。具体目标二：确定是否正常人乳腺上皮细胞可以被混合的人癌前病变或癌细胞刺激进行肿瘤发生和转移。具体目标3：确定缺乏起始癌基因的肿瘤细胞中的独特表达变化。

 DESCRIPTION (provided by applicant): The overall goal of this proposed research is to explore a preliminary observation of non-clonal evolution in cancer metastasis. Breast cancer is most frequently diagnosed cancer in women (except skin cancer) and the second leading cause of cancer death after lung cancer. Breast cancer arises from the epithelial cells of the breast ductal tree. We have previously developed several somatic mouse models of breast cancer evolution by adapting the RCAS-TVA method for introducing oncogenes into somatic tissues. This model also allows us to genetically track the small number of breast epithelial cells that suffered the initial oncogenic mutation in a field of fully developed mammary gland in vivo. Using this method to introduce either Wnt1 or ErbB2 to initiate the formation of triple-negative and HER2 breast cancer subtypes, the two most aggregative cancer subtypes of women, we found surprising evidence of non-clonal evolution of cancer. We found that within the resulting mammary tumor, there exists a minor population of cells that histologically appears to be carcinoma cells, but surprisingly lacks the provirus DNA and the initiating oncogene. Furthermore and even more unexpectedly, we found that many of the metastatic foci in the lungs also lack the provirus DNA and its oncogenic protein product. These unexpected preliminary data suggest a provocative hypothesis that as the initially mutated breast epithelial cells evolve to cancer, the neighboring normal breast epithelial cells that did not suffer the initiating oncogenic mutation can be instigated by the mutated cells to become cancerous and even metastatic. To test this non-clonal hypothesis for breast cancer metastasis, we will pursue three aims: Specific Aim 1: To verify our preliminary mouse model finding that the normal mammary epithelial cells can be stimulated by adjacent oncogene-activated mammary cells to undergo tumorigenesis and metastasis. Specific Aim 2: To determine whether normal human breast epithelial cells can be instigated by admixed human premalignant or cancerous cells to undergo tumorigenesis and metastasis. Specific Aim 3: To define the unique expression changes in the tumor cells that lack the initiating oncogene.