Use of Transgenic Mouse Model with a Regulatable Estrogen Receptor Alpha (ER) to Study the Role of ER in Mammary Gland Development and Cancer
Abstract
Estrogen (E2) is required for the development of breast cancer, but there are few animal models to study its mechanism of action in vivo. We hypothesize that the timing of estrogen receptor a (ER alpha) action is crucial in normal mammary gland development and tumorigenesis. Therefore, a transgenic mouse model with a regulatable ER alpha is being generated. In vitro, a mutant ER alpha (525L) has a severely attenuated response to endogenous estradiol (E2) but a wild-type (WT) response to diethylstilbestrol (DES) . E2 binding was decreased in 525L (Kd l2.5nM) compared with WT (Kd O.lnM), but DES binding was comparable (Kd 0.04 and O.O3nM respectively). Gene targeting was used to insert 525L into the WT ER gene. Screening for the construct in 350 ES cell clones is underway. The mutant 525L ER alpha discrimination in transcriptional response to DES and E2 appears to result from differences in ligand binding affinity. The resultant transgenic mouse will enable us to study how the timing of ER activation modulates normal mammary maturation and the development of mammary cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2002
- Accession Number
- ADA410769
Entities
People
- Sonia L Sugg
Organizations
- Medical College of Wisconsin