PROGENITOR CELLS AND ONCOGENE TARGETS IN BREAST CANCER

描述（由申请人提供）：乳腺癌随着突变在乳腺上皮中积累而发生，乳腺上皮由祖细胞及其分化后代、乳腺上皮细胞和肌上皮细胞组成。乳腺癌的发生也受到妇女生育史的影响。年轻时足月妊娠可以降低风险，尽管其机制仍是一个谜。我最近发现，MMTV-Wnt-1转基因小鼠中出现的乳腺肿瘤表达祖细胞标志物，并含有上皮和肌上皮肿瘤细胞，这意味着肿瘤来自共同的祖细胞。相比之下，在MMTV-Neu转基因小鼠中产生的乳腺肿瘤中，祖细胞标志物不存在，肿瘤细胞仅为上皮细胞。因此，我们假设Wnt信号转导可能比成熟细胞更有效地转化乳腺祖细胞，而Neu信号转导可能转化分化的细胞，或转化祖细胞但不能阻止或主动诱导其分化。此外，分化的Wnt表达细胞似乎在模拟哺乳后退化过程中丢失，这表明了妊娠保护作用的解释。然而，不同的致癌途径作用于不同的靶细胞，对妊娠和退化产生不同反应的机制尚不清楚。 为了研究这些问题，我们已经适应了禽逆转录病毒RCAS转移到体细胞乳腺细胞的遗传改变，选择性地作出易感感染的转基因表达的RCAS受体TVA。 由于这种方法在选定的时间将癌基因传递到选定类型的个体体细胞，与生殖系转基因不同，我们现在可以研究不同的癌基因如何在不同的时间影响不同的细胞类型。因此，我们建议：（1）确定生命早期的妊娠周期是否会保护乳房免受携带活化Wnt而非Neu的分化上皮细胞的累积。(2)为了确定具有激活的Wnt信号传导的祖细胞是否将在退化中存活并演变成混合细胞谱系的肿瘤，而具有激活的Neu信号传导的祖细胞也将在退化中存活但仅演变成上皮谱系的肿瘤。(3)鉴定一种可引起祖细胞异型增生和肿瘤形成的Wnt诱导的旁分泌因子。 拟议的工作将提供机制的理解，乳腺癌的启动是如何共同决定的特定致癌突变，突变发生的细胞的分化状态，并由个人的生殖史。该方法还具有一般应用，在体内分析乳腺癌的演变和进展中的其他遗传事件的贡献。

DESCRIPTION (provided by applicant): Breast cancer develops as mutations accumulate in the breast epithelium, comprised of progenitor cells and their differentiated progeny, mammary epithelial cells and myoepithelial cells. Breast carcinogenesis is also affected by the reproductive history of the woman. A full-term pregnancy at a younger age reduces risk, though the mechanism is a mystery. I have recently found that the mammary tumors arising in MMTV-Wnt-1 transgenic mice express progenitor cell markers and contain both epithelial and myoepithelial tumor cells, implying that the tumors arose from a common progenitor cell. In contrast, in mammary tumors arising in MMTV-Neu transgenic mice, progenitor cell markers are absent and the tumor cells are only epithelial. We thus hypothesize that Wnt signaling may transform mammary progenitor cells more effectively than mature cells, whereas Neu signaling may either transform differentiated cells, or transform progenitor cells but fail to prevent or actively induce their differentiation. Furthermore, differentiated Wnt-expressing cells appear to be lost during simulated post-lactational involution, suggesting an explanation for the protective effect of pregnancy. However, the mechanisms by which different oncogenic pathways act on different target cells to give different responses to pregnancy and involution are not known. To investigate these issues, we have adapted the avian retrovirus RCAS to transfer genetic alterations into somatic mammary cells that are selectively made susceptible to infection by transgenic expression of the RCAS receptor TVA. Since this method delivers oncogenes to individual somatic cells of a selected type at a selected time, unlike germline transgenes, we can now study how different oncogenes affect different cell types at different times. We therefore propose: (1) To determine whether a cycle of pregnancy in early life will protect the breast from accumulating differentiated epithelial cells bearing activated Wnt but not Neu. (2) To determine whether progenitor cells that have activated Wnt signaling will survive involution and evolve into tumors of mixed cell lineages, while progenitor cells that have activated Neu signaling will also survive involution but evolve into tumors of the epithelial lineage only. (3) To identify a Wnt-inducible paracrine factor that can cause dysplastic proliferation and tumor formation in progenitor cells. The proposed work will provide mechanistic understanding on how breast cancer initiation is jointly determined by the specific oncogenic mutation, by the differentiation status of the cell in which the mutation occurs, and by the reproductive history of the individual. The methodology also has general applications in analyzing the in vivo contributions of other genetic events in breast cancer evolution and progression.