Molecular Switch Is Linked To Common Breast Cancer

Although precise data isn't available, LABC may account for 50 percent or more of breast cancers among women in developing countries, and 30 percent of breast cancers among socially disadvantaged and minority women in the United States. This type of cancer is defined by a large tumor that is about 2 inches or larger in diameter, about the size of a plum, when first diagnosed. The cancer may have spread into surrounding lymph nodes or other tissues. However, it hasn't yet spread to more distant areas in the body.

Without treatment, fewer than 20 percent of patients with LABC are living five years after their diagnosis. Unfortunately, even with appropriate treatments, this cancer is deadlier than other types of breast cancer that are detected earlier.

Locally advanced breast cancers are typically large tumors that, remarkably, have rarely spread to form additional tumors in distant sites in the body when they are discovered. However, locally advanced breast cancer patients often have a high level of treatment failure as the disease is often detected at an advanced stage. Previous work has shown that for large tumors to progress they must develop their own blood supply through a process known as tumor angiogenesis. Angiogenesis is often triggered as the expanding tumor cells move away from the existing blood supply and are deprived of oxygen, a condition known as hypoxia.

The ability of tumors to develop their own vasculature limits their growth and is regulated at different levels of genetic control. Now, a research study led by Drs. Robert J. Schneider and Silvia C. Formenti of New York University School of Medicine presents new evidence demonstrating how an unorthodox second pathway in protein synthesis plays a key role in controlling the translation of genetic messages (mRNAs) for factors that orchestrate angiogenesis, the tumor response to hypoxia and progression of tumors to form large locally advanced breast cancers. "Our study shows that an unusual molecular switch occurs in the machinery that carries out synthesis of proteins that are essential for angiogenesis and tumor progression," explains Dr. Schneider.

Drs. Schneider and Formenti led the new study which found that two molecules were unusually abundant or "overexpressed" specifically in locally advanced breast cancers. Further analysis in mice revealed that the molecules orchestrated a switch in the use of messenger RNA, a kind of ferry service that carries information for making proteins. This switch, the researchers found, occurs when tumors become starved for oxygen, a condition known as hypoxia. The switch permits the selective expression of proteins that are required for tumors to carry out angiogenesis, the process of developing a blood supply. It also enables tumors to grow to a large size and to progress.

"The identification of the molecular switch and its importance for development of locally advanced breast cancer reveals realistic targets for the development of new therapeutics to block tumor angiogenesis and progression in breast and possibly other cancers," says Dr. Schneider.

The new study is published in the November 9, 2007 issue of the journal Molecular Cell. The authors of this study are: Drs. Formenti and Schneider; Ksenia Karpisheva; Steve Braunstein; Carolina Pola; Judith Goldberg; Tsivia Hochman; Herman Yee; Joan Cangiarella; and Rezina Arju. All are affiliated with NYU School of Medicine.

With funding from the Breast Cancer Research Foundation and the Department of Defense, Robert J. Schneider, Ph.D., the Albert B. Sabin Professor of Molecular Pathogenesis, and Silvia C. Formenti, M.D., the Sandra and Edward H. Meyer Professor of Radiation Oncology and Chairwoman of Radiation Oncology, and their colleagues at NYU School of Medicine have made LABC the focus of a coordinated effort to understand the disease.