Caitlyn Lightle ’23 & Meenal Cascella ’23

One in eight women in the United States will be diagnosed with breast cancer in her lifetime. It is the most common cancer among women globally, with more than 2 million new cases each year according to the Susan G. Komen Foundation. With statistics like these, breast cancer has impacted individuals on every level. In order to defeat such a pervasive disease, we need critical research that aims to understand DNA mutations that cause breast cancer. TCU biology professor Mikaela Stewart is innovating the way we research breast cancer in efforts to transform these harrowing statistics into stories of victory.

The Stewart Laboratory has been working to determine the molecular details of how the BRCA1 protein functions. For the past three decades, researchers have been aware that there is a link between mutations in the BRCA1 gene and an increased risk for breast and ovarian cancer. Stewart says, “This is critical so that we can better predict which mutations people inherit will increase cancer risk and which mutations do not affect the function and thus are perfectly safe…There are thousands of variants of unknown significance in BRCA1, so we aim to provide the knowledge of how the protein works so we can better determine if these variations are detrimental or functional.” If a person knows they have a detrimental mutation, they can pursue a surgery that would reduce their risk of cancer.

Stewart’s research addresses why a BRCA1 mutation increases a person’s risk of breast and ovarian cancer, but not other forms of cancer, such as brain cancer or skin cancer. Her Laboratory and collaborators recently uncovered the body’s logic behind this phenomenon. “We figured out that BRCA1 and one of its partners called BARD1 work together to turn down the expression of other genes that metabolize estrogen into DNA damaging molecules. These molecules are particularly harmful when you carry detrimental mutations in BRCA1 or BARD1 because the damage they cause cannot be efficiently repaired. This makes it more likely that estrogen-exposed tissues will get unrepaired mutations throughout their lifetime that lead to cancer,” Stewart says. By knowing this, researchers can determine if different variations within the BRCA1 and BARD1 genes can impact a person’s risk for cancer.

Stewart is also excited about tackling which of BRCA1’s functions utilize enzymatic activity. She says, “The typical approach to figure this out is to engineer a mutation that breaks the enzymatic activity and see which functions BRCA1 struggles to perform. This has been impossible because mutations we studied broke more than just the enzymatic activity. Now that we understand better how BRCA1 interacts with its target to turn off genes, we have generated a mutant that only affects enzymatic activity toward this target. We are just getting the first data in this week, and it’s so exciting!”

Her work has also positively impacted the students she has mentored and opened doors for the next generation of researchers. Undergraduate senior Caitlin Lightle has been working alongside Stewart as a lab assistant since freshman year. Lightle says, “Working with Dr. Stewart as a research mentor the past couple of years has been a rewarding experience. I have had the opportunity to develop my skills with lab techniques as well as gain experience analyzing and writing scientific literature. Dr. Stewart’s passion for this research is inspiring, and it is evident that she cares about the students she brings into the lab. This project has been an important part of my college experience and has given me a deeper appreciation for the scientific concepts underlying medicine. Knowing that this research can make an impact on the lives of others is encouraging and has motivated me to pursue more research projects in the future.” Undergraduate senior Meenal Cascella emphasized her gratitude to be able to work alongside Stewart. She says, “I’ve really enjoyed working with and learning from Dr. Stewart during these past few years. She’s a great mentor and has taught me so much about the process of conducting research. Through working with her, I’ve learned how to review literature and conduct experiments, as well as write about and present my findings to an audience. With her help, I have been studying an organism called the C. elegans that contains similar genes to the human ones associated with breast cancer. I find this research super exciting because it has the potential to have large impacts on human lives, and I’m grateful to be doing it with such a patient and encouraging mentor.”

Learn more about TCU’s Department of Biology.