Elevated Levels of StAR-Related Lipid Transfer Protein 3 Alter Cholesterol Balance and Adhesiveness of Breast Cancer Cells

Abstract

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.

L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling

“…Furthermore, re-analysis of a tissue microarray comprising 1,212 samples from a Finnish nationwide population-based breast cancer series (FinProg cohort), previously stained for MYO10 (ref. 13) and pSrc Y416 (refs 13, 32), revealed that MYO10 protein levels correlate with Src activity in patient samples (Fig. 6g; Table 1).…”

“…Patient and sample inclusion criteria for FinProg are described in detail elsewhere56. The FinProg series (1,212 samples) was previously stained for pSrc Y416 and MYO10 expression as described earlier1332. From these data a potential association between the expression groups was assessed using the χ 2 -test.…”

The Role of Cholesterol in Cancer

“…STAR and STARD3 are two essential proteins that regulate cholesterol import to the mitochondria (Figure 1B) (20,22). In hepatocellular carcinoma, increased mitochondrial cholesterol content was associated with increased expression of STAR and knockdown increased sensitivity to chemotherapeutic agents (20).…”

“…Decreasing STARD3 levels reduced cell proliferation and increased cell death in HER2-positive breast cancer cell lines while it was ineffective in HER2-negative cells (44). Furthermore, STARD3 overexpression decreased the adhesiveness of breast cancer cells thereby modulating metastases (22). …”

LncSubpathway: a novel approach for identifying dysfunctional subpathways associated with risk lncRNAs by integrating lncRNA and mRNA expression profiles and pathway topologies

“…In addition, lipid metabolism was associated with the luminal A and HER2 subtypes, but not with the other two subtypes. While elevated levels of STAR-related lipid transfer protein 3 may contribute to progression of HER2-positive breast cancers [43], the contributions of lipid metabolism abnormalities to progression in the luminal A subtype requires further study. The above findings suggest that LncSubpathway can identify unique risk lncRNA-related functional groups that correspond to the clinical and molecular characteristics of different breast cancer subtypes.…”