This is how dense breast tissue may lead to cancer

Breast cancer frequently arises in abnormally dense breast tissue, prompting clinicians to monitor women with this tissue type more closely following mammograms. A recent study from the University of California, San Francisco (UCSF) has identified a possible mechanism explaining how this dense environment might facilitate breast cancer development.

Dense breast tissue, which is stiffer than normal tissue, attracts immune cells known as macrophages and triggers them to release chemicals that can damage DNA, thus increasing the risk of cancer. Senior author Valerie M. Weaver and her team, led by postdoctoral scholar Mary Kate Hayward, used genomic data from breast tumors to discover that patients with poorer outcomes showed increased breast tissue fibrosis (scarring), macrophage presence, and DNA mutations.

The researchers then examined tumor samples in the lab, measuring tumor stiffness and analyzing collagen, a protein that can increase tissue stiffness. They found that stiffer tumor regions contained more collagen and shared the same cancer-related characteristics—fibrosis, macrophages, and DNA mutations—as genomic data from other tumors.

Stiffer tumor samples also exhibited higher STAT3 activity, a signaling pathway associated with cancer progression. By growing tumors in gels of varying stiffness, the team observed that the stiff environment stimulated breast cells to activate STAT3, which in turn led to the release of reactive oxygen species (ROS) from macrophages.

Initially, ROS were thought to be short-lived and reactive, making them unlikely to travel far enough from macrophages to damage nearby cells. However, the researchers discovered that ROS caused oxidative damage to fats within macrophages, transforming them into aldehydes—chemicals capable of damaging DNA. Unlike ROS, aldehydes could escape the macrophages and spread to adjacent breast cells, resulting in increased DNA damage.

The findings, confirmed through additional experiments in petri dishes and mouse models of breast cancer, as well as an analysis of human breast cancer biopsies, suggest that dense, fibrotic breast tissue harbors more macrophages, aldehydes, and DNA damage, ultimately leading to more advanced disease. The research provides a potential explanation for why dense breast tissue may promote the formation of new tumors and could pave the way for developing treatments that prevent aldehyde formation in macrophages.