The characterisation of the role of BRCA1 notch signalling and differentiation of breast cells

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

BRCA1 is a key regulator of breast differentiation through activation of Notch signalling with implications for anti-endocrine treatment of breast cancers

Here, we show for the first time, that the familial breast/ovarian cancer susceptibility gene BRCA1 activates the Notch pathway in breast cells by transcriptional upregulation of Notch ligands and receptors in both normal and cancer cells. We demonstrate through chromatin immunoprecipitation assays that BRCA1 is localized to a conserved intronic enhancer region within the Notch ligand Jagged-1 (JAG1) gene, an event requiring ΔNp63. We propose that this BRCA1/ΔNp63-mediated induction of JAG1 may be important the regulation of breast stem/precursor cells, as knockdown of all three proteins resulted in increased tumoursphere growth and increased activity of stem cell markers such as Aldehyde Dehydrogenase 1 (ALDH1). Knockdown of Notch1 and JAG1 phenocopied BRCA1 knockdown resulting in the loss of Estrogen Receptor-α (ER-α) expression and other luminal markers. A Notch mimetic peptide could activate an ER-α promoter reporter in a BRCA1-dependent manner, whereas Notch inhibition using a γ-secretase inhibitor reversed this process. We demonstrate that inhibition of Notch signalling resulted in decreased sensitivity to the anti-estrogen drug Tamoxifen but increased expression of markers associated with basal-like breast cancer. Together, these findings suggest that BRCA1 transcriptional upregulation of Notch signalling is a key event in the normal differentiation process in breast tissue

Three-Dimensional Water Vapor Visualization in Porous Packing by Near-Infrared Diffuse Transmittance Tomography

This work presents a procedure based on two-dimensional and three-dimensional spatially resolved near-infrared imaging to observe temperature and composition maps in gas solid packed beds subjected to effects of aspect ratio and nonisothermal conditions. The technique was applied to the water vapor flow in a fluidized bed and a packed bed reactor and confirmed uneven water vapor flow channeling and temperature distributions in the core packed bed and in the vicinity of the wall due to flow maldistribution. In addition, the heat uptake and local cross-mixing were experimentally ascertained