Breast cancer is the most common cancer in women and the majority of these tumors express estrogen receptor alpha (ER). Patients with ER-positive tumors are treated with hormone therapy (e.g., Tamoxifen, Femara) for years after surgery in order to block the activity of ER and prevent the spread and recurrence of their primary tumor. Hormone therapies are prescribed to approximately 150,000 new women in the United States every year and have benefited many women struggling with breast cancer. Unfortunately, around 25% of women will have a tumor recurrence during their hormone therapy treatment. When tumors that do not respond to hormone therapy arise, they are very difficult to treat, and these women are unlikely to survive for another 5 years. Our hope is to identify treatments that are effective and safe for women with hormone therapy resistant breast tumors. The proposed project aims to address the following overarching challenge defined by the Breast Cancer Research Program: "Eliminate the mortality associated with metastatic breast cancer."

Study Design: It was recently discovered that very specific mutations in ER occur in approximately 25% of hormone therapy resistant tumors, representing approximately 50,000 women worldwide that will be diagnosed with breast cancer metastases that have these mutations during the next year. If we find a way to effectively treat these tumors, then we would prevent approximately one-sixth of breast cancer deaths in the United States. In order to achieve the goal of identifying treatments for these patients, we are using a cutting-edge approach to model resistance in human cells. We plan to introduce specific ER mutations into human cell lines and use the cells as mini-patients as we look for treatments that effectively stop the growth of these tumors. We will focus most of our efforts on trying to identify drugs that are already in clinical use with the hope of quickly moving towards a cure for patients that have breast cancer with mutations in ER.

Objectives: The successful completion of this project will lead to a set of drugs that are promising candidates for safely and effectively stopping the growth and spread of metastatic breast cancer with mutations in ER. It is our hope that this preclinical work will motivate clinical trials and lead to effective and safe treatment options for patients with metastatic tumors within the next 5-10 years. Helping even a subset of patients who develop hormone therapy resistant tumors would represent a major advance in the treatment of breast cancer and improve outcomes for patients faced with this terrible disease.