Abstract
Breast cancer is the most common cancer among women worldwide. We previously showed that early-life exposure to flaxseed (FS) or its components, FS oil (FSO) and secoisolariciresinol diglucoside (SDG), affects the mammary gland (MG) and is associated with the reduction of breast cancer risk during adulthood. However, the underlying mechanisms are not understood. This study aimed to investigate the effect of FS, FSO, and SDG on the MG miRNA signature at a late stage of development. Female C57BL/6 mice, 4-5 weeks of age, were randomized into four groups to receive: (i) basal AIN-93G, (ii) 10% FS, (iii) 3.67% FSO, or (iv) 0.15% SDG. After 21 days, the mice were sacrificed and MG miRNAs were profiled. Diet-specific MG miRNA signatures were identified. Deregulated miRNAs were associated with breast cancer and targeted genes involved in MG development, growth, and cancer. The study allowed for the identification of potential biomarkers or novel therapeutic targets to prevent and/or reduce the risk of breast cancer.
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Key points
Environmental factors such as diet have been shown to alter the expression of mammary gland cancer miRNAs. Recent studies have showed that dietary phytochemicals may inhibit breast cancer through the regulation of miRNAs expression such as n-3 PUFA. To date, no studies have investigated the effect of flaxseed (FS) and its components, FSO (oil) and SDG, on the miRNA expression signature during MG development. The objective of this study was to investigate the effect of exposing female C57BL/6 mice to 10% FS, as well as FSO or SDG found at the level in 10% FS, during MG development on MG miRNA expression signature and to identify potential targets to prevent breast cancer development during adulthood.
A four-miRNA signature (higher miR-1 and miR-210 and lower miR-297c and miR-500 expression) was significantly associated with the FS diet, a different four-miRNA signature (higher miR-30b, miR-324-5p and miR-423-3p and lower miR-382 expression) significantly associated with the FSO diet, and a two-miRNA signature (higher miR-142-5p and miR-1966) significantly associated with the SDG diet. This shows that the effects of FS components on MG miRNA expression are not additive. Here, despite being fed the same amount of SDG, the 10% FS group had relatively higher serum enterolignans concentrations compared to SDG-fed group.
The key findings include the identification of (1) diet-specific MG miRNA signatures, (2) diet-dependent deregulation of selected breast cancer-associated miRNAs, and (3) enriched gene sets targeted by these miRNAs in each dietary intervention group. In the FS group, miR-1 was upregulated. This miRNA is known as a tumor suppressor in breast cancer, but was significantly downregulated in breast cancer compared to non-tumor tissues. In the FSO group, with mice receiving the equivalent amount of 3.67% FSO as in the FS group, both miR-30b and miR-324-5p were upregulated compared to the BD and SDG groups, with no significant changes in the expression levels when compared to the FS group.
It is speculated that FS and FSO dietary interventions could be used either to antagonize breast cancer-associated alterations of selected miRNAs or to prevent their deregulation in the MG during development.
This research is significant, as it provides evidence that FS and its FSO and SDG components have different physiological consequences, which should be considered when used as a preventive or therapeutic agent. Furthermore, by taking a global approach, it suggests a potential mechanism via miRNA for FS to impact developing MG, a mechanism that has only been marginally considered so far.