Abstract
BackgroundEthanol abuse promotes breast cancer development, metastasis and recurrence stimulating mammary tumorigenesis by mechanisms that remain unclear. Normally, 35% of breast cancer is Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)-positive that predisposes to poor prognosis and relapse, while ethanol drinking leads to invasion of their ERBB2 positive cells triggering the phosphorylation status of mitogen-activated protein kinase. StAR-related lipid transfer protein 10 (STARD10) is a lipid transporter of phosphatidylcholine (PC) and phosphatidylethanolamine (PE); changes on membrane composition of PC and PE occur before the morphological tumorigenic events. Interestingly, STARD10 has been described to be highly expressed in 35–40% of ERBB2-positive breast cancers. In this study, we demonstrate that ethanol administration promotes STARD10 and ERBB2 expression that is significantly associated with increased cell malignancy and aggressiveness.Material and methodsWe investigated the effect of ethanol on STARD10-ERBB2 cross-talk in breast cancer cells, MMTV-neu transgenic mice and in clinical ERBB2-positive breast cancer specimens with Western Blotting and Real-time PCR. We also examined the effects of their knockdown and overexpression on transient transfected breast cancer cells using promoter activity, MTT, cell migration, calcium and membrane fluidity assays in vitro.ResultsEthanol administration induces STARD10 and ERBB2 expression in vitro and in vivo. ERBB2 overexpression causes an increase in STARD10 expression, while overexpression of ERBB2’s downstream targets, p65, c-MYC, c-FOS or c-JUN induces STARD10 promoter activity, correlative of enhanced ERBB2 function. Ethanol and STARD10-mediated cellular membrane fluidity and intracellular calcium concentration impact ERBB2 signaling pathway as evaluated by enhanced p65 nuclear translocation and binding to both ERBB2 and STARD10 promoters.ConclusionOur finding proved that STARD10 and ERBB2 positively regulate each other’s expression and function. Taken together, our data demonstrate that ethanol can modulate ERBB2’s function in breast cancer via a novel interplay with STARD10.
Highlights
Ethanol abuse promotes breast cancer development, metastasis and recurrence stimulating mammary tumorigenesis by mechanisms that remain unclear
steroidogenic acute regulatory protein (StAR)-related lipid transfer protein 10 (STARD10) expression was not detectable at protein level, while in Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) positive human breast cancer tissue, it was expressed in 30% of samples (Fig. 1b, right panel)
This data supports the literature which states that STARD10 is overexpressed in 35% of primary human breast cancers and positively correlates with ERBB2 overexpression [16, 20]
Summary
Ethanol abuse promotes breast cancer development, metastasis and recurrence stimulating mammary tumorigenesis by mechanisms that remain unclear. The role of STARD10 as key player in subcellular lipid transfer and cellular signaling regulation has not been clarified yetPhosphorylation is a common modification that regulates the activity of proteins, increasing their local negative charge to promote conformational changes or influencing interaction with protein partners. STARD10 is highly expressed at protein level in mouse mammary tumor, in 35% of primary breast carcinoma and in 64% of human breast cancer cell lines. This data supports the role of STARD10 as lipid binding protein in deregulated cell growth and tumorigenesis. STARD10 was found to be co-expressed with ERBB2 in several breast carcinoma cell lines, suggesting a selective growth advantage and cellular transformation for tumor expressing both proteins [16]. The aim of this study was to investigate the role of STARD10 and ERBB2 cross-talk in breast cancer as consequence of ethanol administration and elucidate the molecular mechanisms
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