title: Elevated levels of StAR-related lipid transfer protein 3 alter cholesterol balance and adhesiveness of breast cancer cells: potential mechanisms contributing to progression of HER2-positive breast cancers.
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.
authors: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland.
authors: Boris
authors: B
authors: Vassilev
authors: Laboratory of Molecular Oncology, Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland.
authors: Harri
authors: H
authors: Sihto
authors: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland.
authors: Shiqian
authors: S
authors: Li
authors: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland.
authors: Maarit
authors: M
authors: Hölttä-Vuori
authors: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland.
authors: Jaakko
authors: J
authors: Ilola
authors: Institute for Molecular Medicine Finland, University of Helsinki, Biomedicum Helsinki 2U, Helsinki, Finland.
authors: Johan
authors: J
authors: Lundin
authors: Institute of Medical Technology, University of Tampere and Tampere University Central Hospital, Tampere, Finland.
authors: Jorma
authors: J
authors: Isola
authors: Institute of Medical Technology, University of Tampere and Tampere University Central Hospital, Tampere, Finland.
authors: Pirkko-Liisa
authors: PL
authors: Kellokumpu-Lehtinen
authors: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
authors: Heikki
authors: H
authors: Joensuu
authors: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland. Electronic address: elina.ikonen@helsinki.fi.
authors: Elina
authors: E
authors: Ikonen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D005784:Gene Amplification / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D044967:Serum / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002784:Cholesterol; D049452:Green Fluorescent Proteins; D006903:Hydroxymethylglutaryl CoA Reductases; D007328:Insulin; D008565:Membrane Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D019061:src-Family Kinases; C105684:STARD3 protein, human