My lab is focused on the genetic dissection of human breast cancer through the use of genetically engineered mouse models and patient-derived tumor xenograft models. For this, we have developed mouse models for BRCA1- and BRCA2-associated hereditary breast cancer and E-cadherin mutated invasive lobular carcinoma (ILC). We have used 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.
Our mouse models for BRCA1-deficient breast cancer develop tumors that are characterized by genomic instability and hypersensitivity to DNA-dama
ging agents and PARP inhibitors. Nevertheless, none of these drugs are curative: tumors grow back after drug treatment and eventually become resistant. Using a combination of functional in vitro screens and in vivo studies, we have found that therapy resistance of BRCA1-mutated tumors can be induced by several mechanisms, including genetic reversion, activation of drug efflux transporters, hypomorphic BRCA1 activity, and rewiring of the DNA-damage response. Therapy resistance of BRCA1-methylated tumors is driven by loss of BRCA1 promoter methylation or by de novo BRCA1 gene fusions created by intrachromosomal genomic rearrangements.
Using forward and reverse genetics in our mouse models of ILC, we have shown that mutations in fgfr2 or PI3K pathway components (pik3ca, Akt or Pten) strongly cooperate with E-cadherin loss in tumorigenesis, leading to development of mammary tumors that closely resemble classical ILC. We have also used in vivo insertional mutagenesis screens to identify mutations that cause resistance to FGFR inhibitors in E-cadherin mutated mammary tumors with overexpression of FGFR2.
To accelerate in vivo evaluation of candidate drivers and drug resistance genes, we have developed novel methods for rapid generation of germline and non-germline breast cancer models. Using embryonic stem cells (ESCs) derived from our conditional mammary tumor models, we can quickly introduce additional gain- and loss-of- function alleles and generate novel tumor models by blastocyst-injection of the manipulated ESCs. Using intraductal injection of CRISPR vectors in mammary tumor models with conditional expression of Cas9, we can test candidate tumor suppressors by in vivo gene editing.
Oncology Programme Seminar