Normal breast tissue at risk for cancer development – the Benz lab investigates a surprising role for fat

Normal breast tissue is usually at least 60% fat, made up of cells called adipocytes. Although fat is typically the largest component of the breast, research has largely focused on the breast’s epithelium tissue, where most tumors arise. This focus is understandable, as a woman in the United States has a better than one in ten chance of developing breast cancer at some time in her life.

For women age 50 or older who are most susceptible to developing breast cancer, only 5-10% of their breast tissue contains the breast glandular epithelium that actually turns into breast cancer. Until very recently, researchers have been almost entirely focused on that vulnerable breast epithelium, trying to understand how breast cancers form and which women are most predisposed to developing breast cancer. Few researchers seem to have noticed the very new evidence that breast adipose tissue, or fat, when metabolically altered, becomes a key nutrient source that drives and accelerates the growth of already established breast cancers.  

A new project in the lab run by Buck professor Chris Benz, MD, pushes well beyond even that cutting- edge concept that altered breast fat is a metabolic driver of existing breast cancers. After doing a deep analysis of tissue samples taken from 151 women who have never had any sign of breast cancer (the samples came from healthy women who volunteered to undergo normal breast biopsies), the Benz team came up with a startling finding:  nearly half of the women donating their breast tissue biopsies possessed altered breast fat like that found around established breast cancers, giving these otherwise healthy donors an unsuspected excess risk of developing life-threatening breast cancer later in life.  

Using a garden analogy to illustrate the process

Dr. Benz says having the metabolically “hot” fat is probably not enough to give rise to breast cancer. A woman would also need to have acquired occasional epithelial mutations known to begin the process of breast cancer development. He describes those epithelial mutations as “seeds”, and the abnormal fat tissue in their breasts as the “soil” that allows those mutations to take root and spread within the glandular epithelium. Dr. Benz, who is also a practicing oncologist at the University of California, San Francisco (UCSF), expands upon this garden analogy. “Seeds are flying around in the air all of the time,” he says. “If they land on concrete nothing happens. If they land on parched earth maybe a few take root; but if they land on fertile soil then they all really take off.”

Dr. Benz is pushing to get the word out about this new fat-associated risk factor to other cancer researchers. His team will do a poster presentation in December at the San Antonio Breast Cancer Symposium, an annual conference that attracts the top researchers and clinicians from around the world.

While much research remains to be done, Dr. Benz says that his deep molecular and microscopic analysis of the normal breast tissue samples, provided by the Komen Tissue Bank, shows that the metabolically altered adipocytes are more plentiful and larger than usual relative to those that function normally.  The “hot” fat also features increased expression of genes that represent pro-inflammatory signals, as well as several important growth factors known to drive breast tumor development and growth. 

Next steps in the research

Dr. Benz is intrigued by the prevention possibility that the altered adipocytes could be reconverted to a normal state. To that end, he is working with surgeons at UCSF who do bariatric surgery aimed at inducing dramatic weight loss in obese individuals. “Research shows that women who undergo bariatric surgery have a sharp decline in their risk for developing breast cancer, and that protective effect can begin within six months of their surgery,” he says. “Why is that? Bariatric surgery causes weight loss in the viscera – the areas surrounding the abdominal organs.  Does that weight loss also impact fat in the breast? Are there signals passed by the blood between the different types of fat? These are questions we need to explore.” In future efforts the Benz team is hoping to analyze breast fat samples taken before and 6 months after bariatric surgery.

Dr. Benz, who was a founding faculty member at the Buck, is also thinking about future screening possibilities to identify women who have altered mammary adipocytes long before any cancer-associated mutations take hold and spread. Acknowledging that it might be too invasive to routinely take biopsies from women without any clinical signs of breast cancer, he says non-invasive devices currently used for bone density scans might be useful in examining breast fat. Current mammogram screens would not be sufficient. He also believes that blood tests might be developed that can detect those signaling factors secreted by the altered adipocytes.

Who would get screened first?

If and when screening becomes feasible, Dr. Benz says there is no doubt who should be screened first: women who have survived breast cancer and currently consider themselves cured of the disease yet remain at some risk for cancer recurrence. Benz says breast cancer patients who have altered fat cells have a three-fold increase in the chance of having their breast cancer come back and dying from it.  “Breast cancer is the second leading cause of death among women in this country,” he says. “There are more than 2.9 million breast cancer survivors in the US and they deserve the best shot at living a long, healthy life. Our hope is that this research will provide a way for them to get that.” 

This new area of research evolved out of the Marin Women’s Study, which Dr. Benz helped initiate in 2006. The study also involved technology and built upon results from The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, which molecularly characterized over 10,000 primary cancers spanning 33 cancer types.  Dr. Benz was among 150 researchers nationwide involved in TCGA.