Exome sequencing - GLI1 induced primary and serially transplanted tumours -Series C

Increased expression of GLI1, the main Hedgehog signalling pathway effector, is related to unfavourable prognosis and progressive disease of some breast cancer subtypes. We used conditional transgenic mice induced to overexpress GLI1 in the mammary epithelium either alone or in combination with deletion of one Trp53 allele to address the role of elevated GLI1 expression in breast tumour initiation and progression. Induced GLI1 expression facilitates mammary gland tumour formation and this was further increased upon heterozygous deletion of Trp53. The GLI1 induced primary tumours were of different murine molecular subtypes, including Normal-likeEx, Class8Ex, Claudin-LowEx and Erbb2-likeEx. The gene expression profiles of some of the tumours correlated well with the human PAM50 subtypes. Whole exome sequencing revealed somatic mutation profiles with only little overlap between the primary tumours. Orthotopically serially transplanted GLI1 induced tumours maintained the main morphological characteristics of the primary tumours for =10 generations. Independent of Trp53 status and molecular subtype, the serially transplanted GLI1 induced tumours were able to grow both in the absence of induced transgenic GLI1 expression and in the presence of the GLI1 inhibitor GANT61. These data suggest that elevated GLI1 expression has a determinant role in tumour initiation, facilitating additional genetic events required for tumour progression. Our transplantable tumour models represent different molecular breast cancer subtypes and will be suitable models for preclinical drug trials stratified by molecular subtype.