The MASLD-breast cancer connection

Do metabolic dysfunction-associated steatotic liver disease (MASLD) and a more severe form of the condition, metabolic dysfunction-associated steatohepatitis (MASH), cause breast cancer?

The short answer to that question…well, there is no good short answer.

The long answer is that there is a body of evidence suggesting an association between MASLD and breast cancer, both from epidemiologic research and mechanistic studies of the two conditions. The adage is correct: correlation is not causation. But associations can be suggestive and merit research and exploration that yields insights even if a case for causation is not clinched.

Corresponding author Natalia Nuño-Lámbarri, of the National Autonomous University of Mexico, and her co-authors reviewed the evidence for a breast-MASLD association in an article published in the International Journal of Molecular Sciences in May. Their conclusion was that while the body of evidence of evidence for a connection is growing, it is insufficient to establish a direct causal relationship. Still, Nuño-Lámbarri and her co-authors suggest that the “integration of metabolic and hepatic assessment into breast cancer risk stratification may represent “an important future clinical direction,” and they float the ideas of identifying “metabolically vulnerable” patients with hepatometabolic biomarkers and coupling interventions that target systemic metabolic dysfunction — weight loss, insulin-sensitizing therapies and glucagon-like peptide 1 drugs — with cancer treatment.

Nuño-Lámbarri and her co-authors conducted their review by searching three well-regarded databases of medical research articles — Pubmed, Scopus and Web of Science — using MASLD and other terms, including the previous name for MASLD, nonalcoholic fatty liver disease (NAFLD), along with terms that identified articles on breast cancer. They centered their search on studies published between 1998 and 2026 but included some seminal studies that were published outside that period.

The epidemiologic evidence of MASLD-breast cancer linkage is growing, but the researchers cautioned that it was difficult to tease out MASLD from all the conditions that coexist with it, including obesity and Type 2 diabetes. They singled out a South Korean study published in 2020 that showed individuals with an elevated fatty liver index had a higher risk of developing breast cancer, independent of body-mass index and other factors that might explain the association. They also cited a study published in JAMA Network Open in 2023 that used data from the Kailuan Cohort Study in China that showed an earlier outset of MASLD was associated with a greater cumulative risk of developing cancer, including breast cancer. A study published last year using UK Biobank data found that MASLD had the strongest association with the development of several cancers among the steatotic liver diseases that the researchers studied. Another study published last year found that MASLD was associated with breast cancer with a poorer prognosis. Nuño-Lámbarri and her co-authors advise caution in interpreting the epidemiologic association, noting the variety of the study designs and the variations in the definition of MALD.

One piece of the puzzle of establishing causation is biologic plausibility. In other words, from what is currently known about two factors, does it make sense that one could cause the other? Nuño-Lámbarri and her co-authors list 13 different pathways that might explain that MASLD has a causative role in breast cancer. They rate the evidence for six of them as strong: insulin resistance and hyperinsulinemia, hormonal dysregulation, adipose tissue-derived estrogen production, chronic low-grade inflammation and the FGF21 axis. Hyperinsulinemia may influence the tumor microenvironment, they note, by promoting anabolic metabolism and crosstalk between adipocytes and tumor cells. High insulin levels may also reduce levels of sex hormone-binding globulin, resulting in higher levels of free estrogen and androgen that can spur on cancer growth. Many studies have linked inflammation to cancer, and Nuño-Lámbarri and her colleagues drew a picture of the cascading effect of activation of Kupffer cells in the liver leading to proinflammatory cytokines leading to the firing up of inflammatory pathways in the breast and other parts of the body that can create the conditions favorable to cancer cells. FGF21 is a hepatokine that may induce a state similar to insulin resistance. The evidence of its role in cancer is still emerging and is based on animal studies, Nuño-Lámbarri and her co-authors write, although they also suggest that FGF21 might be a target for future drug development.

What’s next?

In an acknowledgement that the evidence of a MASLD-breast cancer link is far from rock solid, Nuño-Lámbarri and her colleagues discussion about “future directions” is about improving research strategies. They call for well-designed prospective longitudinal studies that use standardized definitions of MASLD. They said there is a need for a deeper understanding of FGF21 and other hepatokine pathways. They also call for interventional studies and more attention to liver health in cancer care. “The integration of metabolic and hepatic assessment into routine oncologic care may ultimately enable a more personalized and preventive approach to breast cancer management,” they argued.