Obesity raises breast cancer risk and worsens prognosis in postmenopausal women, but the reasons have remained unclear. A new study by researchers from Cornell University and Weill Cornell Medical College explains how obesity changes the consistency of breast tissue in ways that are similar to tumors, thus promoting disease.

The study, involving mice and women, shows that obesity leads to a stiffening of a meshwork of material surrounding fat cells in the breast, called the extracellular matrix, and these biomechanical changes create the right conditions for tumor growth.

Senior author Dr. Claudia Fischbach-Teschl, an associate professor of biomedical engineering, said:

“We all know that obesity is bad; the metabolism changes and hormones change, so when looking for links to breast cancer, researchers almost exclusively have focused on the biochemical changes happening. But what these findings show is that there are also biophysical changes that are important."

The results suggest clinicians may need to employ finer-scale imaging techniques in mammograms, especially for obese women, to detect a denser extracellular matrix. Also, the findings should caution doctors against using certain fat cells from obese women in plastic and reconstructive breast surgeries, as these cells can promote recurring breast cancer.

Co-author Dr. Andrew Dannenberg, professor of medicine and associate director of cancer prevention in the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College, Said:

“These findings provide important new mechanistic insights into the connection between obesity and breast cancer. Importantly, the current results are also likely to be relevant to other obesity-related cancers. A significant challenge and opportunity will be to develop new noninvasive strategies to identify women with abnormal extracellular matrix."

Fat tissue in obese women has more cells called myofibroblasts, compared to fat tissue in normal- weight women. Myofibroblasts are wound-healing cells that determine whether a scar will form.

All cells secrete compounds to create an extracellular matrix, and they remodel and grab onto this meshwork to make tissue. But when myofibroblasts make an extracellular matrix, they pull together, the action needed to close a wound, stiffening the tissue.

But “these are cells in our body regardless of injury,” Dr. Fischbach-Teschl said.

Stiffer Extracellular Matrix

In obese women, there are more myofibroblasts than in lean women, which leads to scarring and stiffening without an injury in the extracellular matrix. Tumors also recruit more myofibroblasts than are found in healthy tissue, which also leads to stiffer extracellular matrix.

In the study, the researchers studied obese mice and found scarred and stiffer extracellular matrices in the absence of tumors. They also examined tumor-free human breast tissues and found the same pattern of stiffness in the matrices of obese women compared with normal-weight women.

Fat tissue is made up of adipose (fat) cells and adipose stromal cells that also contain myofibroblasts. The researchers isolated adipose stromal cells from the breasts of lean and obese mice and used these cells to make matrices.

When tumor cells were added onto the matrix from the obese cells, they grew. Through experiments, the researchers proved the stiffness of this matrix changed a cell’s behavior and promoted tumor growth.

They also found that when calories were restricted in obese mice, myofibroblast content in the mammary fat decreased, suggesting a possible therapy for obesity-related cancer.

Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis Bo Ri Seo, Priya Bhardwaj, Siyoung Choi, Jacqueline Gonzalez, Roberto C. Andresen Eguiluz, Karin Wang, Sunish Mohanan, Patrick G. Morris, Baoheng Du, Xi K. Zhou, Linda T. Vahdat, Akanksha Verma, Olivier Elemento, Clifford A. Hudis, Rebecca M. Williams, Delphine Gourdon, Andrew J. Dannenberg, Claudia Fischbach Science Translational Medicine19 Aug 2015 : 301ra130

Illustration: curly collagen fibers in normal weight mice (left), a stiffer meshwork of straight fibers in obese animals (right). Collagen fibers are labeled magenta, and adipocytes (fat) and inflammatory cells are green. Image credit: Fischbach Lab

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