An intracellular pathway not previously linked to breast cancer is driving a subtype of the disease that is highly lethal and disproportionately overrepresented in African American women, scientists have found.

The pathway regulates how cells identify and destroy proteins and represents a class of genes known as proteasome-targeting complexes. The work shows that basal cancer cells degrade the tumor-suppressor gene p27 by making a new type of proteasome-targeting complex. The gene p27 is one of a handful of proteins expressed in normal cells that act to prevent rapid cell growth, which is indicative of cancer.

Beyond chemotherapy, no specific therapeutic target has been identified for this subtype of cancer, found in between 12 to 15 percent of breast cancers in the general population and up to 25 percent of cases in African American women.

"The mortality rates in this subgroup of cancer are very high," said Timothy Lane, senior author of the paper and a researcher at UCLA's Jonsson Comprehensive Cancer Center. "The possibility that this new proteasome-targeting complex might provide targets for therapeutic intervention is a completely new area for breast cancer research."

Scientists have identified five to seven different subtypes of breast cancer. Basal-like breast cancers currently are among the most difficult to treat.

Targeted therapeutics are available for several subtypes. Women with HER-2-positive breast cancers can receive Herceptin, which, when paired with chemotherapy, extends disease-free survival by more than 50 percent. HER-2-positive women used to have the worst prognoses before Herceptin was developed. They now have the best prognoses, because the drug targets what's broken in the cancer cells driving the disease. Another subtype includes women with estrogen receptor-positive cancers. These patients have several drugs available, such as Tamoxifen, that suppress the actions of estrogen on breast cancer tissue and thus control the disease.

Next, Lane and his team plan to use protein chemistry and genetic tools to uncover the molecular components that participate in this new proteasome-targeting complex, which could identify alterations, like HER-2,  that can be targeted in cancer cells while leaving healthy cells alone. That would give patients with this aggressive cancer subtype a more effective and less toxic option than chemotherapy.

"This research has the potential to identify clinically relevant markers of a large subgroup of human breast cancer and find a novel therapeutic target that could be exploited with appropriate pharmaceutical agents," said Lane, who is a UCLA associate professor of obstetrics and gynecology. "We need a new paradigm to think about how to treat these cancers."

Lane's research also showed that basal-like breast cancer cells are most like breast stem cells, which generate the tissues of the breast. Both, for example, are resistant to chemotherapy and do not express mature breast markers like estrogen receptor. These features make basal-like breast cancers so difficult to treat.

Another mystery Lane and his team hope to focus on is why basal-like breast cancers are overrepresented in African American women. It could be related to genetic features in the patient or to other complex factors, such as access to effective early intervention, Lane said.

Lane is currently working to validate his research in human disease and identify all the components in this molecular pathway.

"We're still missing a couple of the key players. We currently understand the shape and general features of the complex but hope to find all the components in the next couple of years," he said. "It is a great time to be involved in this research."

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