Pathologist uncovers clue in breast cancer paradox

SAN ANTONIO (Sept. 15, 2010) — Pothana Saikumar, Ph.D., an associate professor with The University of Texas Health Science Center at San Antonio, was studying kidney regeneration when he made an important breast cancer finding. The ramifications could extend to women with breast cancers that require the most intense chemotherapy.

Scientists have long known that a small protein Dr. Saikumar was studying, Transforming Growth Factor-Beta (TGF-B), behaves in a paradoxical way. When a cell begins undergoing the transformation into a cancerous state, TGF-B can stop that growth and protects us from developing cancer. But if that cell escapes the TGF-B surveillance, then it will advance into a full-blown cancer cell and TGF-B can help it thrive and spread faster.

“Turning off this ‘treasonous’ action of TGF-B alone may indeed be advantageous,” the pathologist said.

Although TGF-B has received intense scrutiny in the 30 years since its discovery, little is understood as to just how it turns from a tumor suppressor into a tumor promoter. Researchers found that if they suppress TGF-B activity to starve a cancerous tumor, a new tumor is likely to start growing, since the protein’s helpful function in preventing new cancerous development is also switched off.

But Dr. Saikumar, working with postdoctoral fellow Prajjal Singha, Ph.D., found a clue in an obscure protein called TMEPAI, and discovered that the two proteins work together to affect cancer’s growth and spread.

“To our surprise, when we knocked out the TMEPAI, these cancerous cells behaved as if they were almost normal,” he said, although TGF-B’s other signaling functions had been preserved.

The cancer cells with TMEPAI “knockdown” did not cause metastasis. They stopped making substances that built blood vessels to nourish the tumors. The tumors began to shrink.

“All these things were happening by knocking down just one gene,” Dr. Saikumar said. “Now we are looking at the molecular basis for this.”

It was exciting information. More exciting still was that when Dr. Saikumar’s team examined these processes in the laboratory using almost 100 breast cancer tumors, they found the most profound changes in so-called “triple-negative” breast cancers, the kind that require the most toxic chemotherapies.

“There’s a long way to go,” Dr. Saikumar said, “but we think that our findings need to be pursued further to work out more details on how the newly discovered cancer-promoting pathway operates, and how it may lend itself to treatment.”

Dr. Saikumar’s findings were reported in the journal Cancer Research in July.

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The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio is one of the elite academic cancer centers in the country to be named a National Cancer Institute (NCI) Designated Cancer Center, and is one of only four in Texas. A leader in developing new drugs to treat cancer, the CTRC Institute for Drug Development (IDD) conducts one of the largest oncology Phase I clinical drug programs in the world, and participates in development of cancer drugs approved by the U.S. Food & Drug Administration. For more information, visit

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