CSHL Scientists Show How a Protein that Orients Cells in Breast Tissue Prevent Them from Becoming Cancerous

In breast tissue, cells lining the breast’s ducts have a certain shape that is required to maintain both organ structure and function. All breast cancers display a loss of this characteristic organization, but very little is known about the molecules and pathways that regulate tissue structure and the role they play during cancer.

A team of scientists at Cold Spring Harbor Laboratory (CSHL) has now discovered that a protein called Scribble, originally discovered as a cell-shape regulator in fruit flies and worms, is an important regulator of breast cancer. They report that normal function of Scribble protein allows breast epithelial cells to form duct-like structures and resist cancer formation. When Scribble stops functioning, the tissue loses its shape and cancers ensue.

The discovery identifies “a new paradigm for understanding how cancer initiates,” according to CSHL Professor Senthil Muthuswamy, Ph.D., who headed the team that conducted the research, to be published in Cell on Nov. 26. The results also constitute first steps toward identifying an entirely new class of molecules and pathways that can be targeted by anti-cancer therapies to prevent pre-cancerous lesions from turning into malignant tumors.

“Thinking about cancer as a disease that results only due to an increase in cell numbers is too simplistic,” according to Muthuswamy. He points out that proteins that control cell number and regulate cell structure are both critical in cancer development. He therefore proposes that carcinomas - cancers derived from epithelial cells in organs such as breast, ovary, prostate, lung and pancreas - should be approached as a problem of “deregulated morphogenic processes and not just as a disease of increased cell number.”

Many studies aimed at unraveling cancer’s molecular mechanisms use cells cultured on plastic dishes as an experimental platform. “Such models have been quite satisfactory in allowing scientists to analyze mechanisms involved in cell growth” says Muthuswamy. But they don’t allow scientists to capture the three-dimensional organization of cells seen in tissue, including their polarity.

A major enabler for Muthuswamy’s current work is an experimental model system that enables him to grow breast cells in three-dimensional cultures to allow them to form structures similar to those seen in breast ducts and lobules.

How Scribble gets deregulated in cancer remains a mystery. The CSHL team is now addressing the question of how the deregulated Scribble pathway can be targeted for diagnosis and treatment.