Weakening a Stubborn Breast Cancer in its Most Vulnerable Genetic Spots

Taking advantage of a case-rich national cancer database as well as breast cancer tissue biopsied from patients at UT Southwestern Medical Center, Stina Singel, M.D., has found that 92 percent of triple-negative breast cancers have a relatively high expression of two specific genes.

Targeting these two genes for treatment offers the potential to make the most aggressive breast cancer among women more susceptible to new therapeutic compounds. Dr. Singel, a Clinical Instructor of Internal Medicine-Hematology who treats patients when she is not in the laboratory, screened triple-negative tissue samples for the presence of the two genes – TLN1 and KIF14 – whose expression, when diminished, also seemed to improve the chemosensitivity of breast cancer tumor cells.

Her yearlong investigation, reported in the latest edition of the American Association for Cancer Research’s journal Clinical Cancer Research, included working with information from the national Cancer Genome Atlas project as well as with breast cancer tissue biopsied by David Euhus, M.D., Professor of Surgery at UT Southwestern.

Recognizing the pressing need to treat women with this aggressive form of cancer – and offer them more therapeutic avenues – Dr. Singel worked with Jerry Shay, Ph.D., Professor of Cell Biology, and with counterparts in his lab to demonstrate that KIF14 and TLN1 inhibition enhances the therapeutic effect of docetaxel in cases of triple-negative breast cancer – one of the standard chemotherapies for that cancer.

“Now that Dr. Singel has identified a very specific genetic trait of this cancer, the next step is to take advantage of her finding by identifying a new way to knock out these two genes,” Dr. Shay said. “The work that she did to get us this far is labor-intensive and not easy.”

Triple-negative breast cancer refers to any breast cancer that does not express the genes for estrogen receptors, progesterone receptors, or the Her2 protein. Triple-negative breast cancers are generally initially susceptible to chemotherapy. However, complete responses and overall survival rates are poor, making it particularly complicated to find the best chemotherapy.

KIF14 overexpression has also been seen in ovarian and lung cancers, and has been shown to be an independent prognostic marker, while TLN1 is a focal adhesion complex protein. In prostate cancer cell models, previous studies have suggested TLN1 is involved in the spreading of cancers from an originating site, possibly making the latest finding applicable to more than just cases of triple-negative breast cancer.

“Making one of the most relentless and fast-moving breast cancers – triple negative – yield to chemotherapy is what drives me as a physician-scientist,” Dr. Singel said.

The work was supported by the National Cancer Institute, the Welch Foundation, the Cancer Prevention and Research Institute of Texas, and a Komen Foundation postdoctoral fellowship.

Other UTSW scientists involved in the investigation are Dr. Woodring Wright, Professor of Cell Biology and Internal Medicine; Dr. Lawrence Lum, Associate Professor of Cell Biology; Gail Fasciani, research associate in Cell Biology; and Crystal Cornelius and Kimberly Batten, research assistants in Cell Biology.

Please visit the Harold C. Simmons Cancer Center to learn more about clinical services for oncology at UT Southwestern, including highly individualized treatments for cancer at the region’s only National Cancer Institute-designated center.

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The work was supported by the National Cancer Institute, part of the National Institutes of Health (NIH), under grant number CA12345.