Rad51c Is a Tumor Suppressor in Mammary and Sebaceous Glands

iv 1 REVIEW OF THE LITERATURE................................................................................... 1 1.1 Sporadic cancers and hereditary syndromes .................................................. 2 1.1.1 Hereditary breast cancer ............................................................................ 3 1.2 DNA damage and repair: pathways of hereditary breast cancer..................... 4 1.2.1 Homologous recombination ....................................................................... 7 1.2.2 Interstrand cross-link repair ....................................................................... 11 1.3 Functions of RAD51C ...................................................................................... 14 1.3.1 Role of RAD51C in DNA repair .................................................................... 15 1.3.2 Role of RAD51C in genome integrity .......................................................... 17 1.3.2.1 Centrosome number maintenance ..................................................188 1.3.2.2 Telomere protection .......................................................................199 1.3.2.3 Role of RAD51C in cell cycle checkpoints .......................................... 20 1.4 RAD51C is a breast cancer susceptibility gene in humans ...............................22 1.5 Rad51c is a tumor suppressor gene in mice ................................................... 24 1.6 Knock-out mouse models of breast cancer ................................................... 28 2 AIMS OF THE STUDY ............................................................................................. 30 3 MATERIALS AND METHODS .................................................................................. 31 4 RESULTS AND DISCUSSION .................................................................................. 34 4.1 Generation of a conditional knock-out mouse model (I-II)............................ 34 4.2 RAD51C in development and differentiation of sebaceous glands ................ 35 4.2.1 Deletion of Rad51c in mouse sebaceous glands induces apoptosis and transdifferentiation (I and unpublished) ............................................ 36 4.2.2 Defects in the homologous recombination pathway do not recapitulate the Rad51c-deficient phenotype in preputial glands (unpublished) .......... 38