Breast cancer prognoses distinguished by mechanical forces

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, according to a new study. Its findings may lead eventually to new treatments 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 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 precancerous 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," said senior author Valerie Weaver, PhD, professor of surgery and anatomy and director of the Center for Bioengineering and Tissue Regeneration at the University of California San Francisco (UCSF). The study was published in Nature Medicine (2014; doi:10.1038/nm.3497).

In the mouse experiments, the scientists found that tissue stiffening in microscopic scaffolding, known as the extracellular matrix (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 miR-18a, a tumor-promoting molecule.

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.

These findings are of clinical interest because they may lead to earlier identification of certain difficult-to-treat breast cancers. About 60% of breast cancers can be easily identified as a type known as luminal breast cancer, but distinguishing the luminal A subtype (approximately 40% of all breast cancers) from the luminal B subtype (approximately 20% of all breast cancers) is difficult.

On average, women with luminal B breast cancer do not survive as long after treatment without breast cancer recurring, and they are less likely to respond to hormone therapies such as tamoxifen. Lack of a good diagnostic tool results in overtreatment of many luminal A breast cancers, Weaver said.

"The work provides early evidence that miR-18a is a strong predictor of metastasis and poor survival in women with luminal breast tumors, and that it may be used to distinguish luminal A breast tumors from luminal B breast tumors," said Laura Van't Veer, PhD, head of the breast oncology program at the Helen Diller Family Comprehensive Cancer Center at UCSF, and the developer of MammaPrint, a 70-gene test used to predict breast cancer spread.

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