The STARD3 gene belongs to the minimal amplicon in HER2-positive breast
cancers and encodes a
cholesterol-binding
membrane protein. To study how elevated StAR-related
lipid transfer protein 3 (StARD3) expression affects
breast cancer cells, we generated MCF-7 cells stably overexpressing StARD3-green fluorescent
protein. We found that StARD3-overexpressing cells exhibited nonadherent morphological features, had increased Src levels, and had altered
cholesterol balance, as evidenced by elevated
mRNA levels of the
cholesterol biosynthesis rate-limiting
enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and increased plasma membrane
cholesterol content. On removal of serum and
insulin from the culture medium, the morphological characteristics of the StARD3-overexpressing cells changed, the cells became adherent, and they developed enlarged focal adhesions. Under these conditions, the StARD3-overexpressing cells maintained elevated Src and plasma membrane
cholesterol content and showed increased phosphorylation of
focal adhesion kinase. In two Finnish nationwide patient cohorts, approximately 10% (212/2220) breast
cancers exhibited high StARD3
protein levels, which was strongly associated with HER2 amplification; several factors related to poor disease outcome and poor
breast cancer-specific survival. In addition, high StARD3 levels in breast
cancers were associated with elevated
3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA levels and anti-Src-Tyr416 immunoreactivity. These results provide evidence that StARD3 overexpression results in increased
cholesterol biosynthesis and
Src kinase activity in
breast cancer cells and suggest that elevated StARD3 expression may contribute to
breast cancer aggressiveness by increasing membrane
cholesterol and enhancing oncogenic signaling.