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Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

Background: Notch4 is a member of the Notch family of receptors that is primarily expressed in the vascular endothelial cells. Genetic deletion of Notch4 does not result in an overt phenotype in mice, thus the function of Notch4 remains poorly understood.

The genus Cephalorhynchus contains four dolphin species, of which three are classified as Near Threatened or Endangered and one subspecies is close to extinction. Understanding the species' abundance, distributions and habitat preferences is necessary for effective management to prevent further population declines. Heaviside's dolphin C. heavisidii is endemic to the Benguela ecosystem off southwest Africa, and like other Cephalorhynchus species these dolphins produce narrowband high-frequency (NBHF) echolocation clicks with a centroid frequency around 125 kHz. We conducted dedicated visual and acoustic line-transect surveys within and adjacent to the Namibian Islands Marine Protected Area in 2012–2014. Acoustic data were processed in the passive acoustic monitoring software PAMGuard, using the default porpoise click detector and classifier to identify NBHF echolocation clicks. Click detection and classification in PAMGuard included a large excess of false positives, which were easily identified by manual verification of events, and ultimately provided 52 definite detections. The acoustic methods provided data in offshore areas and during overnight periods, but were imperfect and not suitable for ecologically important shallow coastal areas. While demonstrating the utility of passive acoustic monitoring in line-transect surveys targeting Cephalorhynchus species, the study shows that both visual and acoustic methods were needed to collect data throughout the range of Heaviside's dolphin. [ABSTRACT FROM AUTHOR]

The Notch signaling pathway is evolutionarily conserved and is critically involved in the development of species as diverse as worms to mammals. Here we show that the Notch signaling pathway is involved with left-right determination during mouse development. One of the first morphological indicators of left-right determination is heart looping. Disruption of the Delta-like 1 (Dll1) gene, which encodes a ligand for Notch family receptors, results in defects in heart looping. Thirty-two percent of the homozygous Dll1 mutants displayed normal heart looping, while the other 68% exhibited looping defects. The heart looping defects observed in Dll1 homozygous mutants can be further characterized as complete reversal {42%, situs inversus) or variations of ventral heart looping (26%). In addition, 42% of the Dll1 homozygous mutants exhibit a reversal of axial rotation. One possible hypothesis for the laterality defects observed in Dll1 homozygous mutants is a failure of midline integrity. Components of the Notch signaling pathway are expressed in the notochord and floor plate. Currently, no laterality defects have been reported for mutants of any of the four Notch receptors in mammals. However, functional redundancy between the Notch receptors is one possible explanation for this observation. After exploring this possibility, we found that Notch1-Notch2 double homozygous mutants displayed heart looping as well as axial rotation defects. These data indicate that the Notch signaling pathway is involved in left-right determination and that Notch1 and Notch2 possess some functional overlap in this developmental process.

The sensory epithelium within the mammalian cochlea (the organ of Corti) is a strictly ordered cellular array consisting of sensory hair cells and nonsensory supporting cells. Previous research has demonstrated that Notch-mediated lateral inhibition plays a key role in the determination of cell types within this array. Specificallly, genetic deletion of the Notch ligand, Jagged2, results in a significant increase in the number of hair cells that develop within the sensory epithelium, presumably as a result of a decrease in Notch activation. In contrast, the downstream mediators and targets of the Notch pathway in the inner ear have not been determined but they may include genes encoding the proneural gene Math1 as well as the HES family of inhibitory bHLH proteins. To determine the potential roles of these genes in cochlear development, in situ hybridization for Math1 and HES5 was performed on the cochleae of wild-type vs. Jagged2 mutants (Jag2deltaDSL). Results in wild-type cochleae show that expression of Math1 transcripts in the duct begins on E13 and ultimately becomes restricted to hair cells in the sensory epithelium. In contrast, expression of HES5 begins on E15 and becomes restricted to supporting cells in the epithelium. Results in Jag2 mutant cochleae suggest that Math1 transcripts are ultimately maintained in a larger number of cells as compared with wild-type, while transcripts for HES5 are dramatically reduced throughout the epithelium. These results are consistent with the hypothesis that activation of Notch via Jagged2 acts to inhibit expression of Math1 in cochlear progenitor cells, possibly through the activity of HES5. [ABSTRACT FROM AUTHOR]