Stemness suppressors to combat aggressive breast cancers

Smoking is linked to an increased risk of developing aggressive breast cancer. While metastasis is the leading-cause of breast cancer-related deaths, there are still no effective ways of preventing this disease. This is all the more frustrating since many metastases form months or even several years after initial surgery or chemotherapy as recurrent disease. While breast cancer subtypes are useful predictors of the response to therapy they do not adequately identify a tumor’s metastatic potential. My work on normal mammary stem cells important for remodeling the breast during pregnancy led to my recent discovery of a new cancer stem cell (CSC) population associated with aggressive disease in multiple clinical subtypes. This suggests that these cells are important biomarkers of breast cancers likely to progress and potential targets for drug therapy. Importantly, I have identified a key cell survival pathway that, when reversed, may represent a critical vulnerability of these CSCs. Thus, my proposal will test the hypothesis that blocking this pathway represents an Achilles heel for CSCs that will prevent recurrence and metastasis regardless of breast cancer subtype. If successful, my studies would represent an important breakthrough toward the goal of reducing deaths from breast cancer. My approach will incorporate not only more expedient cell lines, but also state-of-the-art patient-derived tumor models in which to test my therapies in cancers that better reflect patient disease, including estrogen receptor-positive (ER+) and triple-negative subtypes. By investigating my therapy in recurrence models post-chemotherapy, I will go the extra mile in attempting to prevent metastasis in a setting that mirrors what patients often experience. Importantly, I plan to re-purpose pre-existing drugs, already approved for use in patients, thereby accelerating the potential for translating successful outcomes from these studies into the clinic. By focusing on eliminating CSCs, my proposed studies represent a sea change in how breast cancer therapies are identified and tested in the laboratory. My unique approach may provide a much-needed means of preventing recurrence and metastasis and reducing mortality in a broad-spectrum of patient breast cancers.