Premium
Alcohol abuse promotes breast cancer development and progression via StarD10 phosphorylation
Author(s) -
Floris Andrea,
Cossu Carla,
Spissu Ylenia,
Tomasi Maria Lauda
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.806.2
Subject(s) - phosphorylation , protein kinase a , mapk/erk pathway , cancer research , kinase , protein phosphorylation , casein kinase 2 , cancer cell , cell growth , chemistry , microbiology and biotechnology , biology , cancer , biochemistry , cyclin dependent kinase 2 , genetics
Background Epidemiological studies demonstrated that ethanol administration promotes breast cancer development and metastasis. Human breast cancer cells or mammary epithelial cells with a high expression of ErbB2 exhibited an enhanced response to ethanol‐stimulated cell invasion in vitro. In addition, ethanol stimulates cell proliferation and triggers different intracellular signaling modulating the phosphorylation status of key proteins as JNK, P38 and ERK. Post‐translational modification by phosphorylation is a common mechanism to regulate the activity of protein, increasing their local negative charge to promote conformational changes or influencing interaction with protein partners. StarD10 is a member of the start protein family well known to be regulated due to Phosphorylation on Serine 284 by Casein Kinase II (CKII); it's a lipid transfer protein with selective binding site to Phosphatidylcholine and Phosphatidylethanolamine. It was found to be co‐expressed with ErbB2 in many breast carcinoma cell lines, suggesting a selective growth advantage for tumor expressing both proteins. The aim of this study was to investigate the role of Phosphorylated StarD10 in breast cancer and its interaction with ErbB2 as consequence of ethanol administration. Methods The experiments were performed using MCF7, MDA‐MB231 human carcinoma cell lines treated with ethanol 100mM. Protein and mRNA levels were analyzed by western blotting/Co‐immunoprecipitation (Co‐IP) and RT‐PCR, respectively. The phosphorylation fraction of StarD10 has been detected by protein purification system columns from cell lysate. Results We found that ethanol treatment increases StarD10 and ErbB2 at both protein and mRNA levels in MCF7 cells. Recombinant proteins were used to demonstrate the direct interaction between StarD10 and ErbB2 and we confirmed this finding by Co‐IP. In addition, ethanol treatment resulted in increased StarD10 and ErB2 interaction. We have established that StarD10 and ErbB2 show a reciprocal regulation. Interesting, we found that both overexpression and silencing of Stard10 induce cell growth and migration suggesting an important role in maintaining cellular homeostasis and potential role of StarD10 in induced‐ethanol breast cancer development and/or progression. In addition, we found that ethanol reduces the phosphorylation status of StarD10 via downregulation of CKII, making it more active. Conclusion The ability of Stard10 to cooperate with ErbB receptors may be independent of its lipid binding function. This novel finding could support the hypothesis of phosphorylation regulates the interaction between ErbB2 and StarD10 and their synergistic action in the neoplastic progression of the breast cancer. This is the first report demonstrating that ethanol can modulate in dynamic manner the phosphorylation status of protein StarD10 in breast cancer cell lines. Support or Funding Information Supported by NIH grant 5 K01 AA022372‐04(Maria Lauda Tomasi)