Tamoxifen is a useful therapy for some, but not all, breast cancer patients with estrogen receptor positive (ER+) tumors. Second line hormonal therapies have limited effectiveness in patients who have failed following a response to tamoxifen treatment for metastatic disease or relapsed after receiving adjuvant tamoxifen therapy. A better understanding of the modifications to current treatment regimens that will extend or restore sensitivity or prolong the therapeutic effect of tamoxifen and other selective estrogen receptor response modifiers (SERMs) is crucial. Recent clinical data suggests that the extent of neoangiogenesis ongoing within a patient's tumor is inversely related to the extent of the therapeutic benefit derived from adjuvant hormonal therapy. Our own preliminary and published data indicate that paracrine effects of angiogenic growth factor production by ER+ human breast tumor cells growing as xenografts in athymic nude mice can reduce the effectiveness of tamoxifen as a cytostatic or cytotoxic agent.

The studies proposed in this project are designed to use these cell lines as model systems to identify the molecular mechanisms responsible for this effect. First of all, ER+ breast tumor cells engineered to overexpress the 165 amino acid form of VEGF-A in a tetracycline regulated manner will be used to determine how angiogenic growth factor production alters the balance of cell proliferation and cell death within xenografts excised from tamoxifen treated mice.

In addition, we will also determine whether mechanisms proposed for acquired tamoxifen resistance in other model systems are operative in the context of angiogenic growth factor overexpression.

Furthermore, we will test the ability of novel VEGFR antagonists that are now in early phase clinical trials to restore tamoxifen sensitivity to VEGF overexpressing xenografts. The ability of these tamoxifen in a NMU carcinogen induced rat mammary carcinoma model will also be explored.

Finally, we will perform a pilot clinical trial to determine if addition of a VEGFR antagonist to the treatment regimen can restore tamoxifen sensitivity to patients with recurrent metastatic breast cancer who either initially responded to tamoxifen treatment or relapsed following adjuvant tamoxifen therapy.