Jos Jonkers Group
Mouse models of breast cancer
My lab is focused on the genetic dissection of breast cancer through the use of genetically engineered mouse models (GEMMs) and patient-derived tumor xenograft (PDX) models. For this, we have developed mouse models for invasive lobular breast cancer (ILC) and BRCA1/2- associated hereditary breast cancer. We use these models to (1) investigate genotype-phenotype relations in mammary tumorigenesis; (2) identify genetic changes underlying breast tumorigenesis; (3) study mechanisms of therapy response and resistance.
Although BRCA-deficient breast cancers are hypersensitive to DNA-damaging therapeutics, they cannot be eradicated and eventually become resistant. Using functional in vitro screens and in vivo studies, we have identified several therapy resistance mechanisms in BRCA1-deficient tumors, including activation of drug efflux pumps, genetic reversion mutations in BRCA1, loss of BRCA1 promoter hypermethylation, BRCA1 gene fusions, hypomorphic BRCA1 activity, and rewiring of the DNA-damage response.
ILCs are hallmarked by somatic inactivation of E-cadherin, but cooperating cancer genes are largely unknown. Using conditional mouse models, we have shown that mutations in p53 or PI3K pathway components (Pik3ca, Akt or Pten) strongly cooperate with E-cadherin loss in ILC formation. We have also used in vivo insertional mutagenesis screens to identify ILC driver genes and mutations that cause resistance to FGFR inhibitors.
To accelerate in vivo validation of candidate drivers and drug resistance genes, we have developed novel methods for rapid generation of germline mouse models using GEMM-derived embryonic stem cells and non-germline models using intraductal injection of CRISPR vectors in Cas9-expressing mice. We have also adopted organoid culture technology from Hans Clevers to identify and validate therapy resistance genes in BRCA-deficient mammary tumor organoids.