Where Are They Now?
Investigation Underway: One Coalition Grant Recipient’s Research on Hormone Therapy Resistance in ER+ Breast Cancer
By Zachary Smith, M.S., PhD Candidate at the University of Rochester School of Medicine and Dentistry, Vertino Lab
Zachary Smith
Can you share a bit about your initial proposal for research when you applied for the Coalition’s grant?
My project focuses on the role of a specific set of epigenetic regulators, the KDM5 demethylases, in estrogen receptor-positive luminal breast cancer (BC), the most common BC subtype. Anti-estrogen hormone therapies are used to treat most luminal BCs and are effective at preventing tumor growth, but unfortunately about half of all luminal BCs eventually become resistant. Previous studies have shown that KDM5s inhibitors increase sensitivity to hormone therapy in luminal BC cells. These results suggest that KDM5 inhibitors could be a potential therapeutic option but a lack of knowledge of exactly how KDM5s increase sensitivity to hormone therapy limits the ability to effectively target KDM5s in luminal breast cancer. I proposed to examine the role of KDM5s in estrogen signaling and hormone therapy resistance with the goal of determining how to most effectively target KDM5s in luminal BC.
What has the Coalition’s grant meant to you? How has it impacted your research?
The Coalition’s grant has funded several key experiments that I completed this year. This has allowed me to do more experiments that have expanded the scope of the project and allowed me to uncover more about how KDM5s function in luminal breast cancer.
Beyond the financial support, the kindness and encouragement that I have received from everyone at the Coalition meant a lot to me. It has been inspiring to get support from people that have been impacted by this disease. This has helped remind me of the value of my work which has helped keep me motivated to continue pushing forward on this project and continue my career as a cancer researcher.
Can you share some updates on where your research currently stands?
I have expanded the project beyond some of my initial proposed goals with KDM5A knockout, KDM5B knockout, and KDM5C knockout luminal BC cells I received from our collaborators in Qin Yan’s lab at Yale University. In these KDM5 knockout cells, I found that upon loss of KDM5A or KDM5B, estrogen-induced gene expression and estrogen-driven growth are maintained and the other two remaining KDM5s are recruited to sites previously bound by the missing KDM5. This matched my previous results in a KDM5B depleted KDM5B knockdown cell line and suggests that upon loss of KDM5A or KDM5B, the other two remaining KDM5s can maintain estrogen signaling. In contrast to KDM5A and KDM5B knockout cells, KDM5C knockout cells have decreased growth rate and decreases in estrogen-induced gene expression. This suggests that KDM5C may be a valuable target in luminal BC independent of KDM5A or KDM5B, although further experiments are still needed to fully characterize the effects of KDM5C loss.
What motivates you most as a researcher?
We are currently in a time of tremendous innovation in biological science, and I am excited for the opportunities this presents to develop better treatments for cancer patients. I look forward to being a part of utilizing all the incredible recent advances in knowledge and technology to help cancer patients live longer and healthier lives.
Where Are They Now? is a new Coalition Voice segment that will share updates in research from past Coalition grant recipients. To date, the Coalition’s Breast Cancer Research Initiative has awarded more than $1.2 million in seed grants to researchers in New York State. These grants have the potential to fund research that will yield significant medical breakthroughs in the cause, prevention, prevention of metastasis, and cure of breast cancer.
