Mechanical forces driving breast cancer lead to key molecular discovery

The stiffening of breast tissue in breast-cancer development points to a new way to distinguish a type of breast cancer with a poor prognosis from a related, but often less deadly type, UC San Francisco researchers have found in a new study.

The findings, published online March 16, 2014 in Nature Medicine, may lead eventually to new treatment focused not only on molecular targets within cancerous cells, but also on mechanical properties of surrounding tissue, the researchers said.

In a mouse model of breast cancer, scientists led by Valerie Weaver, PhD, professor of surgery and anatomy and director of the Center for Bioengineering and Tissue Regeneration at UCSF, identified a biochemical chain of events leading to tumor progression. Significantly, this chain of events was triggered by stiffening of scaffolding tissue in the microscopic environment surrounding pre-cancerous cells. The stiffening led to the production of a molecule that can be measured in human breast cancer tissue, and which the researchers found was associated with worse clinical outcomes.

"This discovery of the molecular chain of events between tissue stiffening and spreading cancer may lead to new and more effective treatment strategies that target structural changes in breast cancers and other tumors," Weaver said.

In the mouse experiments, Janna Mouw, PhD, a UCSF associate specialist who works in Weaver's lab, found that tissue stiffening in microscopic scaffolding known as the extracellular matrix, or ECM, increases signaling by ECM-associated molecules, called integrins. The integrins in turn trigger a signaling cascade within cells that leads to the production of a tumor-promoting molecule called miR-18a.

Unlike most cellular signaling molecules thus far studied by scientists, miR-18a is not a protein or a hormone, but rather a microRNA, another type of molecule recognized in recent years to play an important role in the lives of cells. The miR-18a dials down the levels of a protective, tumor-suppressing protein called PTEN, which often is disabled in cancerous cells, leading to abnormal biochemical signaling that can promote cancer growth.

Stiffening of the tissue microenvironment in tumors

Weaver is a trained biochemist, and has been a trailblazer in the study of tissue mechanics and cancer for 15 years. Mouw is a mechanical engineer. The newly reported UCSF discovery highlights the importance of mechanical forces in the development of cancer, which usually is thought of in biochemical terms.

Armed with modern lab techniques, Weaver has made many discoveries about the mechanical and structural properties of tumor tissue and the stiffening that can occur. For example, she was the first to identify the cross-linking of structural elements within the ECM as a precursor to cancer progression.