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Obesity and cancer

How obesity promotes triple-negative breast cancer

Obesity reprograms mammary adipose tissue macrophages increasing the incidence and severity of triple-negative breast cancer

A study from researchers at the University of Chicago has reported that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumour formation, increasing the incidence and severity of triple-negative breast cancer (TNBC).

Triple-negative breast cancer (TNBC) is a type of breast cancer that is particularly difficult to treat. None of the three most appealing drug targets - the estrogen receptor, the progesterone receptor and human epidermal growth factor receptor 2 - are present on TNBC cells.

"These cancers can be particularly aggressive," said study author, Dr Lev Becker, an assistant professor in the Ben May Department for Cancer Research at the University of Chicago. "For patients with TNBC, there are few therapeutic options. The survival rate is quite low. And the cancer tends to be dramatically elevated in patients who are overweight or obese."

The research, ‘Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer’, was published in the Journal of Experimental Medicine.

"Current treatment of breast cancer patients ignores the ongoing obesity epidemic," said study co-author, Dr Marsha Rosner, the Charles B. Huggins Professor in the Ben May Department for Cancer Research. "In order to take this into consideration, we need to help patients lose weight or identify new drug targets that would be effective in obese cancer patients."

Unfortunately, once the cancer has been detected there may not be time to lose weight prior to treatment.

"So our bottom line," explained Rosner, “is to promote weight loss as a cancer prevention measure, incorporate weight loss as a component of therapy for patients with breast cancer, and develop specific drug targets that could be leveraged to address the obesity component of the disease."

The researchers show that obesity reprograms macrophages -- scavenger white blood cells that can devour invaders such as bacteria, viruses or tumor cells -- into pro-inflammatory, metabolically-activated macrophages. Instead of fighting breast cancer, these immune cells actually promote it.

"Our studies, in mice and humans," Becker added, "implicate these metabolically-activated adipose tissue macrophages." They accumulate in mammary adipose tissue. They release interleukin 6, a pro-inflammatory cytokine which can fuel tumorigenesis. And they thrive on obesity.

Interleukin 6 binds to a receptor on the surface of existing cancer cells. That can create "an even more aggressive stem cell phenotype," Becker said. "These cancer stem cells are able to encourage tumor growth and metastasis, enabling them to travel to other sites." Patients with advanced or metastatic cancer have higher levels of IL-6 in their blood, which is correlated with poor survival rates.

Obesity, the study authors wrote, is a pathological state that "facilitates tumorigenesis by creating tumor permissive conditions in multiple tissues." This suggests that chronic inflammation and its effects on tumorigenesis may be reversed by targeted anti-inflammatory therapies or by weight loss. Indeed, the researchers found that inducing weight loss in obese mice by feeding them a healthier low-fat diet reversed macrophage inflammation and TNBC tumor formation in mammary fat, even though their body weight remained elevated. These findings highlight the potential value of weight loss, not only as a preventive intervention but even after patients develop breast cancer.

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