Fall 2010, Issue 12

Understanding, Preventing, and Treating Breast Cancer

Gail Sonenshein, PhD, joined the Department of Biochemistry in 2010. Her research focuses on molecular signaling mechanisms in breast cancer—the “stop” and “go” signals that can turn a normal cell into a malignant one. She and her research group are working on tumor treatment targets within the nuclear factor (NF)–κB activation cascade, tumor suppression by the lysyl oxidase (LOX) propeptide, and tumor prevention by green tea polyphenols.

Sonenshein earned her PhD in biology from Massachusetts Institute of Technology. She did a research fellowship in the Department of Virology at the Institut de Recherches Scientifiques sur le Cancer in Villejuif, France, followed by research associate appointments at Tufts University School of Medicine and then MIT. She joined Boston University School of Medicine and rose to the rank of full professor in 1988. At BU, she was director of the Program in Research in Women’s Health, the Division of Research on Women’s Health, the Breast Cancer Program (Hubert Humphrey Cancer Center), and the Women’s Health Interdisciplinary Research Center. She was co-associate director of the Boston University National Center of Excellence in Women’s Health for seven years.

“I made a decision 10 or 15 years ago to direct the research in my laboratory to women’s health,” says Sonenshein, “and I selected breast cancer as an area because I had been working on cancer in general—oncogenes and how they work.” (An oncogene is a gene capable of causing cancer.) Sonenshein emphasizes that only about 10% of breast cancers are known to be caused by inherited oncogenes; the remaining 90% are believed to be caused by sporadic occurrences, possibly related to exposure to carcinogens or to nutrient deficiencies. Sonenshein and her research group focus primarily on sporadic cancers.

One major research project involves the NF-κB family of transcription factors (proteins that regulate genes). NF-κB transcription factors are needed for proper functioning of the immune system; specifically, they protect B cells from dying. Several years ago, Sonenshein and her research group discovered that these factors also protect breast cancer cells from dying, a finding that has been extended to several other cancers. This discovery made NF-κB a focus for possible cancer treatment.

“NF-κB really is in many ways responsible for the survival and resistance of cancer cells to chemotherapy,” says Sonenshein. “One major aspect of the research in the lab is to look at how NF-κB is protecting [cancer cells]. Also we, and others, found over the years that as cancer cells get more aggressive, they tend to have more and more [NF-κB] components. So part of the question is what genes are these transcription factors regulating, and how is that leading to the more aggressive phenotype of the cancer cell.”

One member of Sonenshein’s research group used microarrays to identify NF-κB–regulated genes that are ON in cancer cells but OFF in immune cells. The group found possible cancer treatment targets that are now being actively pursued. “There’s a wonderful website that a friend of mine, Tom Gilmore who’s at BU, set up,” says Sonenshein. “It lists the structures of the [NF-κB] subunits, the targets, the mouse models that different people have made, things that induce it, diseases that have been connected to it. It’s a wonderful resource.”

A second major project is on a tumor suppressor called lysyl oxidase propeptide (LOX-PP). This suppressor inhibits the Ras oncogene involved in many aggressive cancers that are resistant to drug therapy. An exciting discovery was that LOX-PP did not require an active p53 tumor suppressor in order to inhibit Ras-activated tumor cells. “We don’t know quite why, but it means that LOX-PP has the potential for being a tremendous polypeptide for treatment,” says Sonenshein. LOX-PP inhibits cancer cell growth in cell culture and in animal models. “I have a couple of postdocs working on what proteins it interacts with, what it is blocking specifically, and what stages of signaling are being affected by this. We’re trying to see if we can just deliver this to the tumor cells. Could we maybe make a nanoparticle that delivers it? Could we make a mesenchymal stem cell that delivers it? This would be one area for collaboration.”

A third major project involves studies on green tea. Preliminary results suggest that components of green tea may protect against cancer; in animal studies the tumor burden was reduced by 70% and the tumors had less invasive properties. “When these cancer cells are going to become invasive, they’ll frequently lose a protein that’s on the surface that helps to keep the cells together; it’s called E-cadherin,” explains Sonenshein. “So we looked at the effects of feeding rats green tea. What we discovered was that the ones that had been given the carcinogen and no green tea had almost no E-cadherin left. When we looked at the animals that had been given the carcinogen and green tea, the cells maintained the entire level of E-cadherin on the surface.”

Sonenshein and her research group are currently looking at the effects of green tea on inflammatory breast cancer, so-called because the cancer cells block mammary ducts and cause the skin over the ducts to look red. “It’s a kind of cancer that is highly malignant, it affects younger women more, it affects blacks more,” says Sonenshein. “Many times by the time it’s diagnosed the disease is in its last stages, so it’s really lethal, and there’s very poor treatment available.” One of Sonenshein’s postdocs is looking at the effects of the active component of green tea on inflammatory breast cancer cells. Preliminary results indicate that green tea might help prevent the spread of this cancer.

For more information, please go to The Gail Sonenshein Lab website.