The role of ALDH1A3 in breast cancer progression and cancer stem cell biology

We need to understand why cancer spreads and comes back years later after treatment. This will help treat cancer patients more effectively. Tumors are made up of different cancer cells. Of all the tumor cells, cancer stem cells (CSCs) have the greatest ability to form new tumors and are also very hard to kill. By understanding the biology of CSCs, we will gain new insight into how cancer develops and be able to make new anti-cancer drugs that kill CSCs better, decreasing the chance that the patient's cancer will return years later. Previously, we found that breast CSCs make an enzyme called aldehyde dehydrogenase 1A3 (ALDH1A3). Breast cancer patients with higher levels of ALDH1A3 in their tumors have more aggressive cancer and are less likely to survive in the long term. We have new data showing that ALDH1A3 also drives breast cancer tumor growth and promotes the spread of the cancer by producing retinoic acid (RA). Based on these observations, we propose the following research aims to determine the role of the ALDH1A3/RA pathway in breast cancer progression and CSC biology and if we can treat cancer with drugs that stop ALDH1A3 function. In Aim 1, we will to determine how the ALDH1A3/RA pathway drives breast cancer growth and spread by identifying the other key upstream and downstream factors in the ALDH1A3/RA pathway. In Aim 2, we will determine how the ALDH1A3/RA pathway regulates CSC growth and affects their ability make new tumors. Finally, in Aim 3, we will test if drugs that block ALDH1A3 function in cancer cells stop breast tumor growth and kill CSCs. This proposal will use laboratory assays, animal models and breast cancer patient tumor samples to understand why breast CSCs have the greatest ability to make new tumors and spread the cancer, and how the ALDH1A3/RA pathway contributes to this process. This will make a major impact in both understanding cancer biology and in devising new strategies for more effective treatments for cancer patients