Advancing the Treatment of Triple Negative Breast Cancer

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The road to medical breakthroughs is typically lengthy and arduous, usually beginning in a laboratory and, after painstaking effort, ending up in the marketplace. This is true of the work done by a notable researcher at the Braman Family Breast Cancer Institute at the Sylvester Comprehensive Cancer Center.

In her molecular oncology laboratory, Karoline Briegel, Ph.D., and her team have identified a molecular determinant that may explain Triple Negative Breast Cancer’s (TNBC) aggressiveness and resistance. More importantly, Dr. Briegel is investigating if inhibiting this protein in human TNBC cells in mouse models in vivo can weaken primary tumor formation and metastasis. This holds therapeutic promise for a deadly cancer. More than 50% of TNBC tumors have proven to be resistant to chemotherapy.
“It’s a very good biomarker and correlates with cancer stemness,” says Dr. Briegel, associate professor in the Department of Surgery who is also an investigator at the Tumor Biology Program.

“There is a lot of potential there for it to become a therapeutic target not just for TNBC but also for other aggressive cancers.”

To understand the importance of this discovery, one must first understand the biology of breast cancer in general and TNBC specifically. Triple Negative Breast Cancer gets its name because it doesn’t have any of the receptors commonly found in breast cancer. Hence, it tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein.
This means the growth of the cancer is not fed by the two hormones or the HER2 protein and therefore does not respond to hormonal therapy or medicines that target HER2 protein receptors.
There are, of course, the usual treatments for TNBC, but unlike other breast tumors, the success rate is low. For example, about 35% of TNBCs respond well to chemotherapy, says Dr. Briegel, but most “are either resistant immediately or after a period of treatment. The tumor grows back. It’s like a mushroom. It’s also highly metastatic.”
In fact, TNBC is particularly dangerous because these breast cancers have a very high potential to metastasize.TNBC usually spreads to such organs as the lung, liver, or brain. Other breast cancers tend to spread to the bone and are more treatable.
Only 15% of breast cancers are identified as TNBC, yet they account for more than one-third of breast cancer deaths. TNBC’s aggressiveness and treatment resistance “often culminates in the patient’s death within 3 to 5 years despite treatment,” Dr. Briegel adds.

TNBC is also more prevalent in young women and African American women.

“It’s devastating because so many [patients] are young mothers who have their whole lives ahead of them,” she says.
It is precisely these factors that first attracted Dr. Briegel to TNBC research. Scientists now know that the aggressiveness of TNBC (like other equally belligerent cancers) is due to a subset of tumor cells known as cancer stem cells. These stem cells fuel tumor growth and metastases because they are able to “self-renew.” They’re also more capable of escaping the primary tumor and traveling through the body to distant organs— and to survive chemotherapy, too.
As a post-doctoral student almost two decades ago, Dr. Briegel discovered the protein that now has served as the basis for so much of her work. After mining data from studies of more than 1,000 primary breast tumors, she found that about 50% of Triple Negative Breast Cancer shared the Limb-Bud-and-Heart (LBH) protein, which predicts poor clinical outcomes.
As a new protein, “we knew close to nothing about it. We didn’t know what it did, if it was important or even how it was regulated,” she recalls. Searching for those answers, as they relate to the WNT signaling pathway, has informed her work thus far.
The WNT signaling pathway is a form of cell communication system, with proteins passing information into a cell through cell surface receptors. This cell-to-cell communication (either within the same cell or from nearby cell to cell) plays a crucial role in normal stem cell regulation and the formation of cancer, as it drives cancer stem cells. Yet, no cancer stem cell-specific therapies have been approved.
After years of persistence and inspiration in the lab, Dr. Briegel and her team found that the protein she had discovered, LBH, operates downstream of the WNT pathway and is a key controller of mammary stem cell renewal and maintenance. Without LBH, TNBC would likely not be able to renew itself or spread so easily.

“Blocking the function of this protein suggests it is a putative therapeutic target,” she says.

She’s especially encouraged because LBH, unlike other WNT pathway genes, doesn’t seem essential for homeostasis. “It only becomes essential when WNT signaling becomes hyperactive as in cancer,” she adds. Therefore, attacking it would likely not affect other cell functions.

The discovery of LBH’s role in tumor formation, while crucial in the fight against TNBC, is still in its infancy.

It may be years before such vital information translates into actual treatment. Dr. Briegel, however, is hopeful. Her team collaborates with breast cancer surgeons, pathologists, and oncologists to translate their findings into real-world application.
“My vision is to develop cancer stem cell-targeted interventions to prevent and reduce the mortality from metastatic breast cancer,” she says.
Dr. Briegel has already traveled part of the long journey there.


Ana Veciana-Suarez, Guest Columnist

Ana Veciana Suarez

Ana is a regular contributor to the University of Miami Health System. She is a renowned journalist and author who has worked at The Miami Herald, The Miami News, and The Palm Beach Post. Visit her website at anavecianasuarez.com or follow @AnaVeciana on Twitter.


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