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Protein preps cells to survive stress of cancer growth and chemotherapy

Beverly Emerson

The image shows in brown color the activation of TGF-Β signaling (left) and p53 levels (right) in a breast biopsy from a patient diagnosed with ductal carcinoma in situ and invasive carcinoma. TGF-Β deactivates the main pathway directing the response to chemotherapeutic drugs, and cellular stress, suggesting a potential new therapy to prevent early stages cancers progression and drug resistance.

A team of scientists in the lab of Beverly M. Emerson has uncovered a survival mechanism that occurs in breast cells that have just turned premalignant—cells on the cusp between normalcy and cancers—which may lead to new methods of stopping tumors. In their study, published in Molecular Cell, the group reported that a protein known as transforming growth factor beta (TGF-Β), considered a tumor suppressor in early cancer development, can actually promote cancer once a cell drifts into a precancerous state. The discovery—a surprise to the investigators—raises the tantalizing possibility that with novel treatment, some cancers might be prevented before they even develop.

TGF-Β molecules are secreted proteins found in most human tissues. They play a number of different biological roles, including controlling cell proliferation and inflammation and assisting in wound healing. The prevailing dogma in cancer research is that TGF-Β signaling keeps cells from morphing into cancer, explains Fernando Lopez-Diaz, a researcher in Emerson's lab who spearheaded the study.

The researchers conducted the study to learn exactly how TGF-Β and p53, a known tumor suppressor, interact in cancer development, examining premalignant as well as cancer cells from breast and lung tumors and matching normal and premalignant breast cells from healthy women. No matter how many different ways they did their experiments, the team found that TGF-Β can interfere with cells' damage responses in premalignant or cancer cells.

"The bad face of TGF-Β emerged within just a few cell divisions away from normality, allowing cells to avoid death," Lopez-Diaz says.

This newfound immortality explains many oncologic mysteries, he says. One is that it sheds light on how premalignant and early cancer cells are able to withstand the assault of chemotherapy and other treatments. It may also explain why 77 percent of breast cancers have a normal p53 gene, and it further suggests a way that cancer cells can use both to metastasize and survive the journey to organs where they set up a new home.

Agents designed to inhibit TGF-Β are already being tested against cancers that have spread, says Emerson. "This study offers both significant insights into early cancer development and a new direction to explore in cancer treatment," she adds. "It would be fantastic if a single agent could shut down both advanced cancer and cancer that is primed to develop."