Do Higher Testosterone and Folate Deficiency Conspire to Increase Breast Cancer Risk?

Dietary folate insufficiency, which disrupts DNA repair, might interact with high circulating testosterone levels to increase women’s risk of developing breast cancer, according to an analysis from Mexico. The findings were published in the journal Nutrition Research.

Women with the highest serum concentrations of testosterone and the lowest dietary intake of folate saw more than 9 times the risk of breast cancer seen among women with the highest folate intake and lowest serum testosterone (odds ratio [OR] 9.18; 95% CI: 2.56-32.88; P = .001), researchers found.

“These findings have important public health implications with respect to reducing the risk of the most frequent cancer in women worldwide,” reported Luisa Maria Sanchez-Zamorano, SciD, of the Population Health Research Center, National Institute of Public Health, in Morelos, Mexico, and co-authors. “Our results support the hypothesis of an interaction between a high free serum concentration of testosterone and a low dietary intake of folate. The mechanisms of this interaction need to be further investigated.”

The case-control study subgroup analysis included data from 342 postmenopausal women with breast cancer and 294 controls and statistically controlled for age, place of residence, time since menopause, socioeconomic status, smoking status, alcohol consumption, breastfeeding history, body mass index (BMI), family history of breast cancer and diabetes, physical activity, and dietary factors such as caloric intake and Western dietary patterns. 

The risk of breast cancer increased with higher serum testosterone levels and, independently, with lower levels of dietary folate. There were also “some indications” that the joint effect of testosterone and folate was synergistic, they reported.

Previous research has shown that testosterone is associated with breast cancer, particularly among postmenopausal women. But it is unclear whether that is because of direct testosterone effects on tumor cells or an association with increased estradiol levels, the authors wrote. 

“Folate intake insufficiency leads to disturbances in DNA replication and DNA repair,” they noted. “Some epidemiological studies have shown that dietary folate intake has a protective effect against the risk of breast cancer.”

Folate plays important roles in gene methylation, not only in DNA synthesis. Folate deficiency has been tied to other cancer types as well, but high levels of circulating folate have been found to be associated with increased prostate cancer risk. 

The case-control study design cannot rule out confounding or inverse causation, such as tumor effects on hormone metabolism, the authors cautioned.

“Our results suggest improving dietary intake recommendations not only for women during pregnancy but also for postmenopausal women,” the authors concluded. 

References:

Synergistic action of folate intake and testosterone associated with breast cancer risk
Luisa Sánchez-Zamorano-Angélica Angeles-Llerenas-Aaron Salinas-Rodríguez-Eduardo Lazcano-Ponce-Isabelle Romieu-Edelmiro Pérez-Rodríguez-Lourdes Flores-Luna-Gabriela Torres-Mejía - Nutrition Research - 2019