Serum VLDL levels are associated with premenopausal breast cancer risk

A recent study based on a large Norwegian population cohort shows that increased serum levels of very-low density lipoproteins (VLDLs) are associated with a decreased long-term breast cancer risk in premenopausal women.

JULIA DEBIK works as a postdoctoral fellow and researcher at the Cancer Imaging and Multiomics research group (CIMORe) and the K.G. Jebsen Center for Genetic Epidemiology, which is based at the Norwegian University of Science and Technology (NTNU) in Trondheim, Norway.

TONE F. BATHEN is a professor who is also affiliated with CIMORe, and GURO F. GISKEØDEGÅRD is an Associate Professor at the K.G. Jebsen Center for Genetic Epidemiology, NTNU, Trondheim, Norway.

Breast cancer is the most common cancer disease among women. Due to established screening protocols and more efficient treatment, breast cancer survival rates have increased during the last decades, bringing the 5-year survival rates above 90% in Norway. The prognosis is highly dependent on the stage of the disease at the time of diagnosis, and tumors may grow for years before they reach a detectable size. Novel methods for early detection and cancer prevention could increase survival and reduce the societal burden of breast cancer. It is necessary to understand the underlying etiology and biological mechanisms leading to breast cancer development and progression to achieve this.

Traditional risk factors of breast cancer

Known risk factors for breast cancer include genetic predisposition, alcohol consumption, smoking, physical inactivity, and obesity. Factors reducing the risk of breast cancer are largely related to reproductive history, such as having children at a young age, having multiple pregnancies, breastfeeding, and early menopause. However, these risk factors alone are not sufficient to accurately predict who will develop breast cancer.

Lipoprotein subfraction analysis provides additional information to traditional lipid measurements

Lipids are important in cell signaling, membrane formation and as a cellular energy source, and lipids circulating in the blood stream reflect both ongoing cellular processes and influence from the environment. Two main forms of circulating lipids in the body are triglycerides and cholesterol, which are transported through the bloodstream in lipoproteins. Lipoproteins carry triglycerides and cholesteryl esters in their inner core, surrounded by a membrane of free cholesterol, phospholipids and apolipoproteins. Different classes of lipoproteins exist, from very-low density (VLDL), low-density (LDL), and intermediate-density (IDL) to high-density (HDL) lipoproteins.

The lipoproteins exist in a range of densities within each class (Figure 1), and conventional methods for lipoprotein quantification do not reflect the delicate density range of the lipoprotein subclasses and the lipids they carry. Previous studies have shown that subfraction analysis, giving detailed information on lipoprotein size and content, provides additional information to that of traditional lipoprotein measurements. Nuclear magnetic resonance (NMR) spectroscopy provides a detailed characterization of lipoprotein subfractions in a blood sample in a fast and reproducible manner.

Lipoproteins are lipid carriers transporting triglycerides and cholesterol to cells throughout the body. Lipoproteins exist in a range of densities. Lipoprotein subfractions analysis provides a detailed image of the concentration of lipoproteins of different densities in the bloodstream and provides important information on what the lipoproteins carry.

Lipoproteins are lipid carriers transporting triglycerides and cholesterol to cells throughout the body. Lipoproteins exist in a range of densities. Lipoprotein subfractions analysis provides a detailed image of the concentration of lipoproteins of different densities in the bloodstream and provides important information on what the lipoproteins carry.

Population biobanks facilitate large-scale prospective studies

The Trøndelag Health Study (HUNT) is a Norwegian longitudinal population health study carried out over four decades and includes questionnaire data, clinical measurements, and biological materials from over 230,000 individuals. The second wave of data collection (HUNT2) conducted between 1995-97 included 65,200 participants. By linking HUNT2 participants to the Norwegian Cancer Registry, we identified 1,199 women who developed breast cancer within a 22-year follow-up period. This provided a unique opportunity to study the association between lipoprotein subfractions and long-term breast cancer risk in a large cohort.

A nested case-control study

We conducted a nested case-control study, comparing the lipoprotein subfraction profiles of 1,199 women who later developed breast cancer and the same number of age-matched women who remained breast cancer free during the 22-year follow-up period. Serum samples were analyzed by NMR spectroscopy to achieve detailed lipoprotein subfraction profiles. We applied logistic regression to test for associations between serum lipoprotein subfractions and long-term breast cancer risk. Models were adjusted for possible confounding factors, including analysis lab, participant age, number of full-term pregnancies, age at menarche, alcohol consumption, smoking status, and body mass index (BMI). The menopausal status was unknown for a large proportion of the cohort and was estimated based on the age at participation in HUNT2.

Several VLDL subfractions inversely associated with long-term breast cancer risk

In our study cohort, 554 cases were classified as premenopausal and 645 as postmenopausal at participation in HUNT2. Postmenopausal women had significantly different lipoprotein subfraction profiles than premenopausal women, with elevated levels of most of the lipoprotein subfractions except for cholesterol and phospholipids in the largest HDL subfractions. Due to the large differences between pre- and postmenopausal women, we performed analyses separately for these groups.

For premenopausal women, we found that several VLDL subfractions were inversely associated with longterm breast cancer risk, including triglycerides, free and esterified cholesterol, and phospholipids in all VLDL particles except for the largest ones. Odds ratios for the different subfractions ranged from 0.77 to 0.83, and associations remained significant after adjusting for confounders. The traditional lipoprotein measures did not show any significant associations, demonstrating the added value of detailed subfraction analysis of lipoproteins. There were no significant associations between lipoprotein subfractions and breast cancer risk for postmenopausal women.

VLDLs are large particles produced and secreted by the liver, transporting lipids from the liver to peripheral tissues and muscles. As estrogen levels play an important role in the regulation of lipid metabolism, we hypothesize that our findings reflect hormonal activity in addition to lifestyle factors.

ORIGINAL PUBLICATION AND COAUTHORS : This article is a summary of an already-published study : Debik et al. Lipoprotein and metabolite associations to breast cancer risk in the HUNT2 study. Br J Cancer 127, 1515–1524 (2022). Coauthors: Julia Debik, Hartmut Schäfer, Trygve Andreassen, Feng Wang, Fang Fang, Claire Cannet, Manfred Spraul, Tone F. Bathen & Guro F. Giskeødegård