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.
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