Abstract
Hyperglycaemia is a common metabolic alteration associated with breast cancer risk and progression. We have previously reported that BRCA1 restrains metabolic activity and proliferative response to IGF-I anabolic actions in breast cancer cells cultured in high glucose. Here, we evaluated the impact of normal physiological glucose on these tumour suppressive roles of BRCA1. Human breast cancer cells cultured in normal physiological and high glucose were treated with IGF-I (0–500 ng/mL). Cellular responses were evaluated using immunoblotting, co-immunoprecipitation, and cell viability assay. As we previously reported, IGF-I induced ACCA dephosphorylation by reducing the association between BRCA1 and phosphorylated ACCA in high glucose, and upregulated FASN abundance downstream of ACCA. However, these effects were not observed in normal glucose. Normal physiological glucose conditions completely blocked IGF-I-induced ACCA dephosphorylation and FASN upregulation. Co-immunoprecipitation studies showed that normal physiological glucose blocked ACCA dephosphorylation by increasing the association between BRCA1 and phosphorylated ACCA. Compared to high glucose, the proliferative response of breast cancer cells to IGF-I was reduced in normal glucose, whereas no difference was observed in normal mammary epithelial cells. Considering these results collectively, we conclude that normal physiological glucose promotes the novel function of BRCA1 as a metabolic restraint of IGF-I actions. These data suggest that maintaining normal glucose levels may improve BRCA1 function in breast cancer and slow down cancer progression.
Highlights
Breast cancer is the most frequently diagnosed cancer among women, accounting for approximately a quarter of all cancers and is the most common cause of cancer death among women [1]
We have previously shown in estrogen receptor (ER)-positive breast cancer cell lines that insulin-like growth factor I (IGF-I) promoted lipogenesis by reducing the association between breast cancer 1 early onset (BRCA1) and the inactive, phosphorylated form of acetyl CoA carboxylase (ACCA), resulting in de-phosphorylation of the enzyme [16]
These experiments were conducted under typical cell culture conditions, the glucose level in culture media is usually higher than normal physiological glucose (5–7 mM), typically at 25 mM, which is in the hyperglycaemic range (>7 mM) and corresponds to severe diabetes [26,33,36]
Summary
Breast cancer is the most frequently diagnosed cancer among women, accounting for approximately a quarter of all cancers and is the most common cause of cancer death among women [1]. Consistent with its role as a negative regulator of fatty acid synthesis, our previous study showed that BRCA1 inhibited lipogenic actions of insulin-like growth factor I (IGF-I) in breast cancer cells [16]. We confirmed our previous findings in high glucose and concluded that IGF-I impairs BRCA1 function by reducing its interaction with phosphorylated ACCA, leading to ACCA dephosphorylation, FASN upregulation, and cell proliferation. These findings were not observed with normal levels of glucose in the current study. The data suggest that maintaining normal glucose levels supports BRCA1 function in restraining IGF-I lipogenic actions and that this may slow breast cancer progression
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