New Clue Emerges in Fight Against Triple-Negative Breast Cancer
A study led by Professor Jill Bargonetti finds mutant protein key to cancer cell survival and may offer new biomarkers for PARP-inhibitor therapy.
Triple-negative breast cancer is an aggressive form of cancer that most often affects Black and Hispanic women and women under 40. There are fewer targeted therapies for this kind of cancer, so it can be difficult to treat.
But new research sheds light on how a mutant protein helps these cancer cells to reproduce and it may yield new targets for treatment.
Published in Molecular Cancer Research, a recent study reveals that this mutant protein, found in most triple-negative breast cancers, plays a vital role in keeping cancer cells alive and dividing.
“A key part of DNA metabolism is the actual replication of the DNA as one cell becomes two,” said senior author Jill Bargonetti (GC/Hunter, Biology, Biochemistry), a renowned cancer researcher and chair of the Molecular, Cellular, and Developmental Biology subprogram at the Graduate Center. “This is critical for the ongoing dividing cancer cells, and the protein poly ADP-ribose polymerase (PARP) helps this process.”
The biologists identified the amino-acid tail of the mutant p53 protein as a crucial connection point that interacts with PARP, which repairs damaged DNA in cancer cells.
This mutant protein can be targeted by existing cancer drugs called PARP inhibitors, they said. “If you inhibit PARP, then the cell dies,” said Bargonetti, the Hasselbach Professor of Biological Sciences at Hunter College.
A targeted approach
The researchers say their findings likely point to new biomarkers for PARP-inhibitor therapy.
“This work suggests that all triple-negative breast cancers with mutant p53 might be treatable with PARP-inhibitor-type therapies that are currently only used for people who have BRCA1 mutations,” Bargonetti said. “So, it could expand the profile, across the board, of people with triple-negative breast cancer who can be prescribed PARP-inhibitor therapy.”
The TP53 gene, which encodes p53, mutates 80% of the time in triple-negative breast cancers, she explained. “But nobody is using that mutant protein as a targeted approach for treating these cancers,” the professor said.
Current biomarkers for targeted therapies include receptors for estrogen, progesterone, and HER2 proteins, which can spur growth in hormone-sensitive breast cancers. Certain medications are prescribed to block these receptors — drugs like tamoxifen, which blocks estrogen receptors, and trastuzumab, which targets HER2 protein receptors.
“If the cancer lacks all three receptors, they’re called ‘triple negative,’” Bargonetti said. “But, we’ve identified a targetable entity. That targetable entity is this interaction between mutant p53 and PARP.”
And this could have implications for other cancers that have mutant p53 proteins, including lung and ovarian cancers, she said.
Working toward a cure
Right now, standard treatments for triple-negative breast cancer are surgery, chemotherapy, and radiation, according to the Breast Cancer Research Foundation. But patients who have BRCA1-gene mutations can be treated with PARP inhibitors.
“They are now standard of care for women who have BRCA1 mutations in their triple-negative breast cancer. However, the only women who are routinely screened for BRCA1 mutations are women of Ashkenazi Jewish descent,” Bargonetti said.
“Other people aren’t treated with PARP inhibitors because they're not BRCA1 mutants, or they're not tested to see if they're BRCA1 mutants,” she said. “All of this set the premise for me to figure out what biomarkers are more generally available that can help increase the profile of people who can get PARP-inhibitor treatments for their triple-negative breast cancers.”
Bargonetti has been working toward a cure for triple-negative breast cancer for over a decade now.
The current study began as part of a Ph.D. thesis project for one of her student mentees — co-lead author Devon Lundine, who has since graduated from the Biology Ph.D.’s Molecular, Cellular, and Developmental Biology subprogram — and finished with the thesis of another study co-lead, George Annor, who recently graduated from the Ph.D. Program in Biochemistry.
Both are now doing postdoctoral work at leading cancer research institutions — Lundine at Memorial Sloan Kettering Cancer Center and Annor at the National Cancer Institute. “These are both amazing Ph.D. students who’ve gone on to find the next step in their careers at premiere cancer research institutions,” said Bargonetti.
The study was funded by the National Institutes of Health and the Breast Cancer Research Foundation. Bargonetti receives her 18th year of grant funding from the foundation this month, the Breast Cancer Awareness Month of October.
Jill Bargonetti: Recognized for Pioneering Science
Among many tributes, Bargonetti was bestowed the Presidential Early Career Award for Scientists and Engineers by President Bill Clinton in 1997, and, in 2001, the Outstanding Woman Scientist Award from the Association for Women in Science. She was inducted into the Bronx Science High School Hall of Fame in 2017.
A former dancer, she teaches a course called Choreographing Genomics, which offers students a way to interpret the flow of gene information through movement.
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