Basal-like breast cancer (BBC) is a highly aggressive type of tumor that often strikes young and African-American women. To better understand its connection to obesity, researchers used two approaches. First, they tested whether the effects of weight loss after weight gain protected against tumors. Second, they investigated whether blocking an oncogenic pathway important to BBC development in both mice and humans – a pathway the laboratory had previously demonstrated to be linked with obesity – would prevent tumor formation. Two papers resulted from these efforts.
Weight loss can reduce tumor onset
The first article, titled “Weight loss reduces basal-like breast cancer through kinome reprogramming,” was published online April 1 by Cancer Cell International.
Co-authors from the Gillings School Department of Nutrition include Makowski, who also is a member of UNC’s Lineberger Comprehensive Cancer Center, as well as lead author Yuanyuan Qin, PhD, former doctoral student, Sneha Sundaram, PhD, postdoctoral fellow, and Luma Essaid, former undergraduate student.
The researchers, who worked with a genetically engineered mouse model, found that BBC tumors presented early in mice that experienced high-fat, diet-induced weight gain. This phenomenon was corrected when mice lost the gained weight prior to tumor onset. This finding shows that it is possible to delay tumor onset through changes in body composition and points to pathways that may be targeted to prevent or reduce cancer growth.
Based on these results, the Makowski lab researchers next analyzed a class of proteins called kinases that transmit signals in cells. The team was able to identify that the activation of key kinases involved in cell growth and metabolism can be regulated by the effects of either a high- or low-fat diet on the mammary gland. These kinases associated with weight gain and weight loss provide novel targets that can be used alone or in combination with weight loss to try to control BBC.
Crizotinib can reduce subsequent tumor burden
In the second recent article, a team of researchers used a pharmacologic approach to attempt to halt the effects of a high-fat diet on aggressive BBC tumor behavior. The Makowski lab had previously shown that the oncogenic hepatocyte growth factor (HGF)/cMet sinaling pathway was responsive to high-fat, diet-induced obesity.
The paper, titled “cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer,” was published online March 19 by SpringerPlus.
Researchers from UNC Gillings Department of Nutrition include Makowski, Qin, Sundaram and Essaid (also co-authors of the first article), as well as Alyssa Cozzo, doctoral student, Ottavia Zattra, undergraduate research assistant, and Alex Freemerman, research associate. Additional authors from the Gillings School are Joseph Galanko, PhD, research assistant professor with the Nutrition Obesity Research Center, and Melissa Troester, PhD, associate professor of epidemiology.
The study, conducted in two phases, first investigated whether crizotinib, a cMet inhibitor, would block or delay tumor onset in lean and obese mice by treating mice before tumors appeared. The second phase tested whether lean and obese mice responded differently to drug therapy after tumors were detected.
The researchers discovered that when mice were treated with crizotinib after the first tumor appeared, fewer subsequent tumors were detected. Crizotinib treatment may have decreased subsequent tumor numbers by reducing the number of blood vessels, which are necessary to supply nutrients for tumor growth.
Using crizotinib prior to tumor development, however, did not prevent tumor onset or growth. Taken together, these findings suggest that the HGF/cMet pathway may not be a viable target for preventing or delaying the onset of obesity-driven tumors, but can prevent subsequent growth once tumors appear.
Crizotinib is already in clinical trials for the treatment of breast and other cancers, such as lung cancer, in humans. Thus, the effects of obesity on crizotinib responsiveness are a crucial consideration for future studies.
Further study needed to better understand protective effects
Because BBC is especially aggressive, with no targeted therapies yet identified for human treatment, additional research is vital.
“What is important about these two papers is that they show that weight loss is more protective against the formation of aggressive tumors than is targeting an obesity-activated pathway with this drug,” said co-author Cozzo.
“These studies beg the question of how the observed protective effects of weight loss or crizotinib inhibition decrease tumor burden,” Makowski added. “We are currently funded to answer precisely this question by testing whether changes to the inflammatory and metabolic milieu in the mammary gland microenvironment will alter cancer formation.”
Further understanding the underlying mechanisms associated with tumors and mammary changes that occur due to weight gain and loss could help identify novel intervention strategies.