The rockefeller university

Event Details

Type

Friday Lecture Series

Speaker(s)

Jos Jonkers, Ph.D., head, division of molecular pathology, Netherlands Cancer Institute

Speaker bio(s)

The Jonkers 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, they have developed mouse models for BRCA1- and BRCA2-associated hereditary breast cancer and E-cadherin-mutated lobular breast cancer. They have used these models to (1) investigate genotype-phenotype relations in mammary tumorigenesis; (2) identify genetic changes underlying breast tumorigenesis; and (3) study mechanisms of therapy response and resistance.

 

The team's mouse models for BRCA1-deficient breast cancer develop tumors that are characterized by genomic instability and hypersensitivity to DNA-damaging 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, Dr. Jonkers has 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, Dr. Jonkers' group has shown that E-cadherin loss strongly cooperates with activation of PI3K or FGFR signaling in mammary tumorigenesis. E-cadherin mutated tumors that overexpress FGFR2 are highly sensitive to FGFR inhibitors but eventually become resistant due to de novo mutations in genes that are causal to the resistance phenotype.

 

Dr. Jonkers did his Ph.D. and postdoctoral research in the group of Anton Berns at the Netherlands Cancer Institute, and did a second postdoc in the group of Allan Bradley at the Wellcome Trust Sanger Institute. He started his own research group at the Netherland Cancer Institute in 2003. He is also professor of molecular experimental oncogenetics and cancer therapeutics at Leiden University. Dr. Jonkers is a member of the European Molecular Biology Organization.

 

Open to

Public

Reception

Refreshments, 3:15 p.m. - 3:45 p.m., Abby Lounge

Contact

Linda Hanssler

Phone

(212) 327-7714

Sponsor

Linda Hanssler
(212) 327-7714
lhanssler@rockefeller.edu

Readings

http://librarynews.rockefeller.edu/?p=3790