Defining the mechanism of ALDH1A3 in breast cancer for the identification of novel therapeutic targets

To treat breast cancer patients more effectively, we need to better understand why cancer spreads and comes back years later after treatment. Breast tumors are made up of different cancer cells. Among them, cancer stem cells (CSCs) have the greatest potential to form new tumors, are very hard to kill and can cause cancer to come back. My lab is investigating these CSCs and the mechanisms that cause cancer to spread. Our long-term goal is to identify new targets for drugs that kill CSCs and stop the spread of cancer. This should decrease the chance the cancer will return. Previously, we found that breast CSCs make an enzyme called aldehyde dehydrogenase 1A3 (ALDH1A3) that promotes tumor growth and the spread of cancer. Patients with higher levels of this enzyme in their tumors are less likely to survive in the long term. We have new data showing that ALDH1A3 promotes breast cancer growth and spread by producing other factors. First, we found a new ALDH1A3-induced molecule (a long non-coding RNA) that is linked to breast cancer growth and CSCs, with potential as a drug target to treat breast cancer. Second, we found that ALDH1A3 increases the production of plasmin; a cell component that helps cancer cells spread by breaking down surrounding structures. Last, by producing retinoic acid, a molecule that controls the expression of many genes in cells, ALDH1A3 causes cancer to spread. We propose to investigate the consequences of these ALDH1A3-induced factors on breast cancer growth and spread, and CSCs. We will use many breast cancer models, from cultured cells to sophisticated mouse models that mimic the patient and act as patient avatars. Our research will give fundamental insight into the mechanisms of how ALDH1A3 promotes cancer growth and spread as well as identifying new ways to treat cancer by killing CSCs. Our findings will make a major impact in understanding cancer and identifying novel drug targets. This will eventually lead to improved outcomes for patients.