One of the most common forms of the disease is ductal carcinoma in situ (DCIS), an early stage, non–invasive breast cancer. If untreated, these tumors become invasive, and are more difficult to treat. DCIS is thought to be the precursor of most invasive breast cancer. The molecular mechanisms underlying how DCIS becomes invasive have remained a mystery. For the first time, scientists at the University of Maryland School of Medicine have unraveled a key mechanism by which this form of breast cancer becomes invasive.

The discovery involves myoepithelial cells, which make up an outer layer of the breast, and help the organ pump milk. These cells play a crucial role in breast cancer. In the early stages of the disease, when it is not invasive yet, these cells act as tumor suppressors, and keep the disease from spreading. However, with aggressive strains of the disease, these cells transform, and are no longer able to subdue tumor spread. At this point, the cancer becomes invasive and begins to spread.

Until now, the process by which myoepithelial cells go from ally to enemy has remained a mystery to researchers. “This is very exciting,” said the lead researcher on the paper, Qun Zhou, MD, PhD, an associate professor in Biochemistry and Molecular Biology at UM SOM. “Until now we really had no idea what happened to myoepithelial cells on a molecular level that inhibited their cancer–fighting ability.” This discovery could point the way to new treatments that keep myoepithelial cells from being transformed.

The findings were published in the Journal of Biological Chemistry.

In the past, very few researchers had worked on myoepithelial cells, because they are extremely difficult to study. They are hard to isolate, and there are no animal models for them that resemble human cancer development. As a result, researchers must use human myoepithelial cells. Dr. Zhou and his colleagues spent the past several years figuring out how to isolate human myoepithelial cells, and then how to track them once they were isolated.

He and his colleagues took samples of myoepithelial cells from human breast cancer patients. Some of these cells came from patients who had early, noninvasive breast cancer, while other samples came from patients who had invasive breast cancer. They then co–cultured myoepithelial cells with DCIS breast cancer cells. The tumor cells that were combined with regular myoepithelial cells grew at a much lower rate than the tumor cells that were combined with the “tumor–associated” myoepithelial cells, which had been transformed.

Dr. Zhou found that the key component in this process is TGF–beta, a growth factor that plays a role many cancers, and has been found to increase the aggressiveness of DCIS. He identified a two–step process: first, TGF–beta causes tumors to increase production of a molecule known as miR–10b. In turn, MiR–10b inhibits a protein called RB1CC1, which suppresses tumors. So in essence, TGF–beta suppresses the tumor suppressor, and as a result the tumors grow more aggressively. This is the first time this mechanism has been identified.

Dr. Zhou says the next step for his lab is to screen compounds that prevent myoepithelial cells from losing their crucial ability to suppress tumors. He has already identified several likely candidates; eventually, he says, this work could lead to clinical breakthroughs.