The available evidence points to a three stage model of tumor progression in the develpoment of resistance to hormonal therapy. In the first stage, tumors are slow growing and are dependent upon E2 for continued growth. These tumors are distinguished from normal tissue which is also E2-dependent by their clonality and unregulated growth. During the Second, or transition stage, selection for mutants or a generalized adaptation process occurs, and cells gradually are able to grow in the absence of E2. Characteristics of these cells may include overexpressed growth factor receptor and/or Ras, induction of drug resistance and altered E2/ E2 receptor (ER) interactions. These cells, while not requiring E2 for growth, nonetheless remain hormone responsive and regress upon treatment with “pure antiestrogens “ such as faslodex or potent aromatase inhibitors. Thus the term “hormone independent but hormone responsive” has been applied to these tumors to distinguish them from completely hormone independent tumors. Paradoxically, these tumors may respond negatively to high doses of an E2 analogue with tumor regression. Notably, Diethylstilberol has long been used in the clinic as a successful treatment of breast cancer in post-menopausal women. Those likely to respond are older women whose tumors have been deprived of E2 for a long period of time. Thirdly is the stage of complete hormone independence without hormone responsiveness (hormone independent and non-hormone responsive).These cells grow rapidly in the absence of E2, and have upregulated growth factor pathways, and are not influenced by pure anti-estrogens or high dose E2.
Our Projects
1) The mechanisms of hormone resistance.
We use models of cells that have developed resistance to endocrine therapies, in particular estrogen deprived and tamoxifen treated cells. We are examining signaling pathways in these cells to determine why the cells are growing in conditions that normally would suppress growth.
2) Development of therapies for advanced breast cancer.
Based on published observations that advanced breast cancers have upregulated signal transduction pathways, we and others have proposed that inhibition of these pathways might be effective breast cancer therapies. We are conducting pre-clinical trials of novel agents to determine their effectiveness against cellular models of advanced breast cancer. Our ultimate aim is to get effective drugs into the clinic.