Drug combination reduces breast cancer risk and improves metabolic health in rats

Approximately 25% of women in the United States between ages 45 and 60 are at high risk for breast cancer and should consider preventative medication, such as the commonly prescribed drug tamoxifen.

Unfortunately, tamoxifen can cause side effects, including an increased risk for type 2 diabetes in women with excess body weight.

In a study published in JCI Insight, researchers investigated the combined effects of bazedoxifene and conjugated estrogens in rat models as an alternative to tamoxifen.

The BZA/CE combination reduced obesity-related changes in rats, including the number and size of fat cells in breast tissues, and increased the abundance of beneficial gut microbes.

By age 40 and above, many women begin to transition into menopause, which is associated with weight gain and insulin resistance, increasing their risk for breast cancer.

“Women who are at high risk for breast cancer are usually prescribed tamoxifen,” said Erin Giles, associate professor of kinesiology and a member of Rogel Cancer Center and Caswell Diabetes Institute.

“Although it can reduce their cancer risk, tamoxifen also increases hot flashes and, in women who are overweight, it may increase their risk for type 2 diabetes, which discourages many women from taking it.”

Tamoxifen works by blocking estrogen from binding to its receptors on the surface of cells, which inhibits breast tumor growth. However, blocking estrogen also causes hot flashes. 

As an alternative, researchers turned to BZA/CE, which has been shown to influence estrogen behavior.

“These drugs are already approved by the FDA for reducing hot flashes and preventing fracture risk. It is currently being evaluated in a phase 2 trial for breast cancer,” Giles said.

“We wanted to see whether BZA/CE could work as an alternative to tamoxifen for those who are overweight.”

The team studied the impact of BZA/CE on body weight and fat distribution in lean and obese rats over an eight-week period.

“Although it can reduce their cancer risk, tamoxifen also increases hot flashes and, in women who are overweight, it may increase their risk for type 2 diabetes, which discourages many women from taking it.” 

-Erin Giles, associate professor of kinesiology and member of the Rogel Cancer Center and Caswell Diabetes Institute

The treatment reduced both body weight and fat in all treated rats, with more pronounced effects in obese rats.

These animals weighed 19% less than the controls and had reduced body fat, including reduced fat accumulation in their breast tissue.

“The levels of triglycerides and cholesterol were also lower, and the treated rats had lower insulin resistance,” Giles said. 

The researchers also measured the changes in gut microbe compositions and found that BZA/CE-treated rats had increased levels of Faecalbaculum rodentium, which may have helped improve the metabolism in these animals. 

In addition, they identified several genes that were different in both lean and obese rats that had been given BZA/CE.

“Our next steps will be to see if similar genes are altered in women who are taking the drug combination,” Giles said.

“Although we didn’t test each drug alone, our results demonstrate that BZA/CE could be superior to tamoxifen for those with obesity who are also undergoing a transition into menopause.”

Additional authors: Katherine L. Cook, Ramsey M. Jenshcke, Karen A. Corleto, Danilo Landrock, Tara N. Mahmood, Katherine E. Sanchez, Alina Levin, Stephen D. Hursting, Bruce F. Kimler, Barry S Komm and Carol J. Fabian.

Funding/disclosures: This work was supported by the Breast Cancer Research Foundation (BCRF-21-049 to Fabian and BCRF 21-073 to Hursting); NIH/NCI R00CA169430 and NIH/NCI R01CA269726 (Giles); NIH/NCI R25CA203650, KUMC CCSG P30-CA168524, NIH/NCI R35CA197627 (Hursting) and DOD Breakthrough Level 2 Award W81XWH-20-1-0014 (Cook).

Paper cited: “Metabolic and transcriptional effects of bazedoxifene/conjugated estrogens in a model of obesity-associated breast cancer risk,” JCI Insight. DOI: 10.1172/jci.insight.182694.

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