Background: Ethanol 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 methods: We 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.
Results: Ethanol 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.
Conclusion: Our 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.
Digital Object Identifier (DOI)
National Institute on Alcohol Abuse and Alcoholism (NIAAA), Award Number: K01AA022372, Recipient: Maria Lauda Tomasi, PhD.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Floris, Andrea; Luo, Jia; Frank, Jacqueline A.; Zhou, Jennifer; Orrù, Sandro; Biancolella, Michela; Pucci, Sabina; Orlandi, Augusto; Campagna, Paolo; Balzano, Antonella; Ramani, Komal; and Tomasi, Maria Lauda, "Star-Related Lipid Transfer Protein 10 (STARD10): A Novel Key Player in Alcohol-Induced Breast Cancer Progression" (2019). Pharmacology and Nutritional Sciences Faculty Publications. 96.
Additional file 1: Table S1.
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Additional file 2: Table S2.
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Additional file 3: Figure S1.
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Additional file 7: Figure S5.