Although Wnt signaling activation is frequently observed in human breast cancer, mutations in the genes encoding intracellular components of the Wnt signaling pathway are rare. We found that expression of Wnt signaling co-receptor LRP6 is up-regulated in a subset of human breast cancer tissues and cell lines. To examine whether overexpression of LRP6 in mammary epithelial cells is sufficient to activate Wnt signaling and promote cell proliferation, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter. We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of β-catenin from membrane to cytoplasmic/nuclear fractions. Expression of several Wnt-target genes including Axin2, Cyclin D1 and c-Myc was also increased in MMTV-LRP6 mice. More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared to wild-type littermate controls. Several matrix metalloproteinases are up-regulated in MMTV-LRP6 mice that could contribute to the hyperplasia phenotype. Our results suggest that Wnt signaling activation at the cell surface receptor level can contribute to breast cancer tumorigenesis.

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tumors. PBS-PT attribution was likely or plausible in all but 2 events. Although CNS-RN could not be attributed solely to end-of-range effects, 11 (48%) cases occurred in the region of the cervico-medullary junction. Complete resolution of CNS necrosis occurred in all 8 grade 3 patients and in 12 of 15 (80%) grade 1 events. Grade 3 or more severe events were treated with bevacizumab, corticosteroids, or hyperbaric oxygen therapy. Symptomatic resolution was comparable between treatments although bevacizumab showed an advantage for radiographic resolution (HR 4.3,. Factors predictive of symptom resolution were eloquence of the region of necrosis (HR 0.15, 95% CI 0.035-0.67, P = 0.0003) and any chemotherapy exposure (HR 0.16, 95% CI 0.03-0.88, P = 0.034). The probability of true necrosis rate exceeding 5% in brainstem increased from less than 10% to greater than 50% at 58.5CGE to a volume of 0.1cc and 57.7CGE to a volume of 1cc. The probability that the true necrosis rate exceeded 10% in the brain increased from less than 10% to greater than 50% at a dose of 63.1CGE to a volume of 0.1cc. At a volume of 1cc, sparsity of data limited analysis to the less than 50% to greater than 50% probability level, which occurred at 60.5CGE. Conclusion: Incidence of radiation necrosis was consistent with photon historical data. These data will aid the development of PBS-PT delivery guidelines aimed at minimizing CNS necrosis risk for children requiring RT which involves or approximates the CNS.

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