Breast cancer is genetically and clinically heterogeneous. Triple negative breast cancer (TNBC) is a subtype of breast cancer that is usually associated with poor outcome and lack of benefit from targeted therapy. We used microarray analysis to perform a pathway analysis of TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), low density lipoprotein receptor-related protein 6 and transcription factor 7 (TCF7) was observed in TNBC, and we directed our focus to the Wnt pathway receptor, FZD7. To validate the function of FZD7, FZD7shRNA was used to knock down FZD7 expression. Notably, reduced cell proliferation and suppressed invasiveness and colony formation were observed in TNBC MDA-MB-231 and BT-20 cells. Study of the possible mechanism indicated that these effects occurred through silencing of the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of b-catenin and decreased transcriptional activity of TCF7. In vivo studies revealed that FZD7shRNA significantly suppressed tumor formation, through reduced cell proliferation, in mice bearing xenografts without FZD7 expression. Our findings suggest that FZD7-involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC, and thus, FZD7 shows promise as a biomarker and a potential therapeutic target for TNBC.

Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2α (HIF-2α) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down-regulation of EPAS1 contributes to the molecular basis of Tibetans’ adaption to high-altitude hypoxia.

SUMMARYIn the zebrafish spinal cord, two classes of neurons develop from the lateral floor plate: Kolmer-AgduhrЉ (KAЉ) and V3 interneurons. We show here that the differentiation of the correct number of KAЉ cells depends on the activity of the homeobox transcription factor Nkx2.9. This factor acts in concert with Nkx2.2a and Nkx2.2b. These factors are also required for the expression of the zinc-finger transcription factor Gata2 in the lateral floor plate. In turn, Gata2 is necessary for expression of the basic helix-loop-helix transcription factor Tal2 that acts upstream of the GABA-synthesizing enzyme glutamic acid decarboxylase 67 gene (gad67) in KAЉ cells. Expression of the transcription factor Sim1, which marks the V3 interneurons in the lateral floor plate, depends also on the three Nkx2 factors. sim1 expression does not require, however, gata2 and tal2. KAЉ cells of the lateral floor plate and the KAЈ cells located more dorsally in the spinal cord share expression of transcription factors. The functional connections between the different regulatory genes, however, differ in the two GABAergic cell types: although gata2 and tal2 are expressed in KAЈ cells, they are dispensable for gad67 expression in these cells. Instead, olig2 and gata3 are required for the differentiation of gad67-expressing KAЈ cells. This suggests that the layout of regulatory networks is crucially dependent on the lineage that differs between KAЈ and KAЉ cells.

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