A majority of breast cancers are hormone-responsive and will require estrogen for growth, and respond to hormonal therapy that blocks estrogen receptor action. Breast tumors lacking estrogen receptor fail to respond to antiestrogen therapy yet require estrogen for tumor initiation. To address directly the importance of breast tissue aromatase in initiation and progression of breast cancer, we have generated aromatase transgenic mice (MMTV-aromatase) and shown that aromatase overexpression resulted in the induction of hyperplastic and dysplastic lesions and they are persistent even without circulating estrogens. Aromatase transgenic mice form ER-positive mammary tumors when exposed to DMBA within four to five months. To our knowledge, this is the first in vivo model that clearly demonstrated the direct involvement of breast tissue aromatase/estrogen in tumorigenesis. An ideal hormone-responsive breast cancer model should give rise to both ER positive and negative tumors. However, there is no such model. To address this issue we have crossed MMTV-aromatase transgenic mice that form estrogen-dependent ER-positive tumors with MMTV-neu which forms ER-negative tumors in response to estrogen. Double transgenic mice show increased proliferation even at very young age (twelve weeks) and increased TGF beta (5 fold), EGFR (2 fold), cyclin D1 (∼ 10 fold), and estrogen receptor alpha levels as well as other biochemical differences. Ongoing studies are focused on determining tumor incidence, estrogen receptor status of all tumors and potential use of chemoprevention approaches with letrozole or EGFR tyrosine kinase inhibitor (AEE788) alone or combined. (Supported by NIH/NCI grant CA75018)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]