Nav: Home

Scientists discover key enzyme in breast cancer proliferation, treatment resistance

March 12, 2019

CHAPEL HILL, NC - Basal-like breast cancer is the most aggressive and difficult-to-treat subtype of breast cancer, and it largely overlaps with the triple-negative classification of the disease. Patients are in dire need of improved therapies that attack the underlying cellular features of these types of breast cancer.

Now scientists at the UNC School of Medicine and the UNC Lineberger Comprehensive Cancer Center have uncovered a possible reason why these cancers are so aggressive. In lab experiments, the researchers found that an enzyme called USP21 promoted proliferation of basal-like breast cancer and is upregulated in a significant percentage of patient tumors.

The discovery, published in Cell Reports, offers researchers a much-needed target for new therapies to battle aggressive subtypes of breast cancer.

"We think USP21 could not only drive basal-like breast cancer in patients, but could represent a new, future target for therapeutic intervention," said senior author Michael Emanuele, PhD, associate professor of pharmacology and UNC Lineberger member. "We also think targeting USP21 could sensitize cancer cells to therapies already in clinical use to treat patients with this disease."

In cancer cells, proteins called transcription factors control the rate at which genetic information is copied from DNA to messenger RNA inside cells. This transcription is crucial for the proper completion of the cell cycle and cell proliferation, including for cancer cells. One of these transcription factors is called FOXM1, which has been found in significant quantities in basal-like breast cancer (BLBC). Despite its importance in normal and cancer cell cycles, scientists have lacked a complete understanding of the mechanisms that regulate FOXM1.

Using an RNA interference-based screening technique to determine regulators of FOXM1 abundance, Emanuele and colleagues found that the enzyme USP21 increased the abundance and stability of FOXM1. The more USP21 in cells, the more FOXM1 was protected during the cell cycle. When the researchers depleted USP21, they noticed a major decrease in the proteins involved in FOXM1's transcriptional network and a significant delay in cell cycle progression.

In their paper, first author Anthony Arceci, PhD, a graduate research assistant in the Emanuele lab, and colleagues show that USP21 depletion sensitized basal-like cancer cells and tumors to paclitaxel - a front-line therapy in BLBC treatment. USP21 is the most frequently amplified enzyme of its class in BLBC patient tumors, and its amplification coincided with the upregulation of FOXM1. This research finding suggests USP21 plays a major role in the proliferation and potential treatment of FOXM1-high, USP21-high basal-like cancer.

"We found that USP21 is commonly upregulated in basal-like, triple-negative breast cancers," Emanuele said. "We think it's possible to develop a drug to inhibit USP21 in the future, to trick the cancer cells into destroying FOXM1 and stopping cancer cells from continuing to grow and proliferate."

The Emanuele lab is further testing these findings is additional animal models of breast cancer to validate USP21 as a potential drug target. The lab also plans to test compounds to inhibit USP21.
-end-
Other authors of the Cell Reports paper, all at UNC-Chapel Hill during this research, are postdoctoral fellows Thomas Bonacci, PhD, and Xianxi Wang, PhD, research technician Kyle Stewart, former graduate student Jeffrey Damrauer, PhD, and Katherine Hoadley, PhD, assistant professor of genetics and UNC Lineberger member.

The University Cancer Research Fund at UNC-Chapel Hill, the Susan G. Komen Foundation, the National Institutes of Health, and the American Cancer Society funded this research.

University of North Carolina Health Care

Related Breast Cancer Articles:

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.
Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.
Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.
More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.
Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.
Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.
Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.
Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.
Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.
Does MRI plus mammography improve detection of new breast cancer after breast conservation therapy?
A new article published by JAMA Oncology compares outcomes for combined mammography and MRI or ultrasonography screenings for new breast cancers in women who have previously undergone breast conservation surgery and radiotherapy for breast cancer initially diagnosed at 50 or younger.
More Breast Cancer News and Breast Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.