Hudis Highlights Interplay Between Inflammation, Obesity, and Breast Cancer

Clifford A. Hudis, MD, FACP

Although obesity is associated with a higher risk of breast cancer in postmenopausal women, the underlying cause of this link is not completely understood. In a discussion at the Miami Breast Cancer Conference, Clifford Hudis, MD, suggested that the increased risk might be a consequence of inflammation that often accompanies obesity.

“There is an obesity/inflammation/aromatase axis that may help to explain the paradox of increased incidence of ER-positive postmenopausal breast cancer [associated] with obesity,” said Hudis, who is chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, and a professor of Medicine at Weill Cornell Medical College.

Hudis’s specific hypothesis is that in obese women, “There [are] elevations of the [proinflammatory mediators] PGE₂, TNF-α, and IL-1β, which, we know from other work, leads to elevated aromatase expression both in breast tissue and in visceral fat.”

He explained that the elevated aromatase expression leads to increased estrogen synthesis and that higher estrogen levels in the blood are associated with an increased breast cancer risk in postmenopausal women.

Hudis and his colleagues first tested their inflammation hypothesis in mouse models. The research involved 40 mice, 20 of which were given a real or a sham ovariectomy to induce menopause. The mice received either a low-fat diet (10% kcal from fat) or high-fat diet (60% kcal from fat). The mice were divided into four equal groups: low-fat (no surgery), low-fat (ovariectomy), high fat (no surgery), high fat (ovariectomy).

The results showed that in mice with diet-induced obesity, inflammation increased in both the mammary gland and visceral fat.

There were two mechanisms by which this increased inflammation was detected. The first was an increase in the levels and activity of the proinflammatory mediators TNF-α, IL-1β, and Cox-2, which is a surrogate for PGE₂.

“The simple take-home is that as weight goes up in these animals, inflammation goes up, as measured by these markers,” said Hudis.

The other mechanism was that the mice developed histologic evidence of inflammation in the form of crown-like structures (CLS), which consist of dead or dying, generally enlarged adipocytes, surrounded by phagocytic macrophages.

Following this initial research, Hudis and colleagues next sought to determine whether the findings from the mouse models would translate to actual patients. They assessed breast tissue from 30 women who were undergoing mastectomy. The cancers were primarily noninvasive—mostly risk reduction surgeries or contralateral mastectomies.

In the analysis, CLS of the breast was found in nearly 50% (14 of 30) of the patient samples. “The incidence of these crown-like structures clearly spikes with overweight and obese body mass indices, and is relatively uncommon in those who were lean,” said Hudis. The severity of breast inflammation correlated with adipocyte size (P = .01) and BMI (P <.001).

The researchers continued their efforts following these results. “We’ve now expanded this effort to hundreds more and these relationships largely hold, although they are a bit more linear than this,” said Hudis.

Hudis framed the significance of his research in terms of what he described as an “unprecedented rate of obesity developing globally.”

“There is an unprecedented change in the phenotype of Americans, and indeed most Westerners, that has been evolving since around the 1950s. The average American currently consumes about 20% more calories per day than they did in the 1950s,” said Hudis.

As has been reported, the incidence of obesity in the United States is greatest in the South; however, the rates are increasing across the entire country. “By 2030, the Robert Wood Johnson Foundation has projected that a full 60% of the citizens of [the] Southern states will be morbidly obese…and there will be no states in the country where there is lower than a 40% incidence of obesity,” said Hudis.

Against this backdrop, Hudis described the implications of his research for practicing clinicians. Specifically, he said that the results thus far suggest that targeting the obesity/inflammation/aromatase/axis through lifestyle interventions in postmenopausal women with a high BMI “could be worthwhile.”

References

1. Subbaramaiah K, Howe LR, Bhardwaj P, et al. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila). 2011;4(3):329-346.
2. Morris PG1, Hudis CA, Giri D, et al. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila). 2011;4(7):1021-1029.

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