Cancer clue. Mice injected with breast cancer cells making lots of a long strand of RNA called HOTAIR developed 10 times as many lung tumors as controls (left) did.

Adapted from Gupta et al., Nature, 464 (15 April 2010)

Stiff breast tissue in obese women may raise cancer risk

It’s long been known that obesity makes women more prone to breast cancer, but the reasons are unclear. Now researchers have found that tissue surrounding breast cells is “stiffer” in obese mice and women, and that this tissue difference in the rodents spurs the growth of cancer cells. For women, the work suggests, losing weight may reshape fat tissue and lower the chances of getting cancer. On the other hand, the growing practice of using fat from obese women for reconstructive surgery of their breast may pose a risk that had been overlooked until now.

Obesity is associated in general with cancer, but the link with breast cancer is especially striking: In one recent large study, the most overweight women were at a 58% higher risk than women of normal weight. One explanation is that fat tissue produces estrogen that can fuel breast cancer cell growth after menopause, when the ovaries stop making estrogen. But the mechanics of the scaffolding that surrounds breast cells—the extracellular matrix—may also matter.

Recent mouse studies have found that a stiffer extracellular matrix triggers the production of proteins that promote the growth of precancerous breast cancer cells. This may help explain why women with dense breasts are also at higher risk for breast cancer. Other studies have shown that when people become obese, their fat tissue tends to build up fibrous, scarlike pockets of tissue.

These studies did not directly examine whether these fibrous pockets affect the local stiffness of breast tissue, and if such changes drive cancer growth. To explore that question, a team led by Cornell University biomedical engineer Claudia Fischbach first showed that female mice that were obese, because of genetics or a high-fat diet, had more fibrous mammary fat pads with straighter collagen fibers than those seen in lean mice (see image). Mechanical testing showed that the straighter fibers reflected a stiffer extracellular matrix between breast cells. The researchers also found a surplus of myofibroblasts, a type of cell involved in wound healing that shapes the structure of collagen and other matrix proteins. When the Cornell team cultured human breast cancer cells on matrix deposited by fat-derived cells from obese mice, the cancer cells grew faster than they did on the matrix of cells from slimmer mice.

The researchers found similar structural differences in fat tissue biopsies from the breasts of obese and lean women, they report today in Science Translational Medicine. The results suggest that the pockets of stiffer extracellular matrix in the breasts of obese women contribute to tumor growth as well as to more aggressive cancers, Fischbach says: “People always think it’s all about soluble factors, chemicals. It’s also about this interplay with physical parameters.”

The news wasn’t all bad: When Fischbach’s team put obese mice on a diet, their mammary fat tissue had fewer myofibroblasts, suggesting losing weight could make a woman’s fat tissue structure more normal and lower her breast cancer risk. At the same time, the study raises questions using a woman’s own fat from elsewhere in her body to reconstruct breasts after a mastectomy. Fat tissue from obese women might raise the risk of a tumor recurring, Fischbach suggests.

Biochemist Valerie Weaver of the University of California, San Francisco, who led previous studies linking tissue stiffness and breast cancer growth, calls the paper “very important” because it finds a novel mechanism linking obesity with breast cancer. Mammograms often can’t detect dense tissue in obese women because it is hidden by fat cells, Fischbach says. The small, local areas of stiff tissue found in the new study are particularly likely to be missed, she adds. So new detection methods may be needed to diagnose these potential cancer-promoting hot spots.