B-Raf deficiency impairs tumor initiation and progression in a murine breast cancer model.

Copy number gains, point mutations and epigenetic silencing events are increasingly observed in genes encoding elements of the Ras/Raf/MEK/ERK signaling axis in human breast cancer. The three Raf kinases A-Raf, B-Raf, and Raf-1 have an important role as gatekeepers in ERK pathway activation and are often dysregulated by somatic alterations of their genes or by the aberrant activity of receptor tyrosine kinases (RTKs) and Ras-GTPases. B-Raf represents the most potent Raf isoform and a critical effector downstream of RTKs and RAS proteins. Aberrant RTK signaling is mimicked by the polyoma middle T antigen (PyMT), which activates various oncogenic signaling pathways, incl. the RAS/ERK axis, in a similar manner as RTKs in human breast cancer. Mammary epithelial cell directed expression of PyMT in mice by the MMTV-PyMT transgene induces mammary hyperplasia progressing over adenoma to metastatic breast cancer with an almost complete penetrance. To understand the functional role of B-Raf in this model for luminal type B breast cancer, we crossed MMTV-PyMT mice with animals that either lack B-Raf expression in the mammary gland or express the signaling impaired B-RafAVKA mutant. The AVKA mutation prevents phosphorylation of T599 and S602 in the B-Raf activation loop and thereby activation of the kinase by upstream signals. We demonstrate for the first time that B-Raf expression and activation is important for tumor initiation in vivo as well as for lung metastasis. Isogenic tumor cell lines generated from conditional Braf knock-out or knock-in mice displayed a reduction in EGF-induced ERK pathway activity as well as in proliferation and invasive growth in three-dimensional matrigel cultures. Our results suggest that B-Raf, which has been hardly studied in the context of breast cancer, represents a critical effector of the PyMT oncoprotein and invite for an assessment of its functional role in human breast cancer.

Smoking, alcohol, diabetes, obesity, socioeconomic status, and the risk of colorectal cancer in a population-based case-control study.

PURPOSE: Although previous research has identified factors that may determine willingness to participate in research, relatively few studies have attempted to quantify the impact non-participation may have on exposure-disease associations. The aims of this study were to (a) investigate the associations between smoking, alcohol, diabetes, obesity, and socioeconomic status and the risk of colorectal cancer in a case-control study (59.7 and 47.2 % response fractions among cases and controls, respectively); and (b) perform sensitivity analyses to examine the possible influence of non-participation. METHODS: Logistic regression was used to estimate the exposure-disease associations. We then investigated the associations between various demographic and health factors and the likelihood that an individual would participate in the case-control study and then performed two sensitivity analyses (sampling weights and multiple imputation) to examine whether non-participation bias may have influenced the exposure-disease associations. RESULTS: The exposures alcohol, smoking, and diabetes were associated with an increased risk of colorectal cancer. We found some differences between cases and controls when examining the factors associated with the participation in the study, and in the sensitivity analyses, the exposure-disease associations were slightly attenuated when compared with those from the original analysis. CONCLUSION: Non-participation may have biased the risk estimates away from the null, but generally not enough to change the conclusions of the study.