PROGENITOR CELLS AND ONCOGENE TARGETS IN BREAST CANCER

描述（由申请人提供）：乳腺癌的发展是由于突变在乳房上皮中积累，包括祖细胞及其分化的后代，乳腺上皮细胞和肌上皮细胞。乳腺癌的发生也受到妇女生育史的影响。年轻时足月妊娠可降低风险，尽管其机制仍是个谜。我最近发现在MMTV-Wnt-1转基因小鼠中产生的乳腺肿瘤表达祖细胞标记物，并且包含上皮和肌上皮肿瘤细胞，这意味着肿瘤起源于一个共同的祖细胞。相比之下，在mmtv - new转基因小鼠中产生的乳腺肿瘤中，没有祖细胞标记物，肿瘤细胞仅为上皮细胞。因此，我们假设Wnt信号可能比成熟细胞更有效地转化乳腺祖细胞，而new信号可能转化已分化的细胞，或者转化祖细胞但不能阻止或积极诱导其分化。此外，分化的表达wnt的细胞似乎在模拟的哺乳期后复合体中丢失，这可能解释了怀孕的保护作用。然而，不同的致癌途径作用于不同的靶细胞，从而对妊娠和复旧产生不同反应的机制尚不清楚。

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.