Premium
GLI1‐induced mammary gland tumours are transplantable and maintain major molecular features
Author(s) -
Norum Jens Henrik,
Frings Oliver,
Kasper Maria,
Bergholtz Helga,
Zell Thime Helene,
Bergström Åsa,
Andersson Agneta,
Kuiper Raoul,
Fredlund Erik,
Sørlie Therese,
Toftgård Rune
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32522
Subject(s) - mammary gland , pathology , gli1 , medicine , biology , cancer , microbiology and biotechnology , hedgehog , breast cancer , signal transduction
Increased expression of GLI1, the main Hedgehog signalling pathway effector, is related to unfavourable prognosis and progressive disease of certain 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‐like Ex , Class8 Ex , Claudin‐Low Ex and Erbb2‐like Ex . The gene expression profiles of some of the tumours correlated well with the PAM50 subtypes for human breast cancer. 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 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; however, additional genetic events are required for tumour progression.