Alcohol consumption promotes the development of human cancers and environmental factors play an important role in the etiology. Epidemiological studies indicate that alcohol consumption not only increases breast cancer risk, but also enhances the progression and the aggressiveness of existing breast tumors. Nonetheless, the mechanism by which alcohol contributes to breast tumor initiation or progression has yet to be established. ErbB2 is a member of epidermal growth factor receptor family. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis. We have previously demonstrated that over-expression of ErbB2 sensitized breast cancer cells to alcohol-induced tumor promotion. Recently, we identified a novel component in ErbB2 signaling pathways that may regulate cancer cell aggressiveness, the p38?. We hypothesized that alcohol enhances NOX-dependent production of ROS which activates ErbB2 or MKK6. The activation of ErbB2 and MKK6 causes selective phosphorylation of p38? which recruits SAP97/DLG. The activated SAP97/DLG promotes epithelial to mesenchymal transition (EMT), increase cancer stem cells (CSC) population and invasiveness of breast cancer cells. This leads to an enhanced aggressiveness. There will be three specific aims.
Specific Aim 1 will determine the role of p38? in alcohol- induced aggressiveness in vitro.
Specific Aim 2 will investigate the mechanisms underlying alcohol-induced p38? activation as well as the mechanisms how p38? mediates aggressiveness of breast cancer cells.
Specific Aim 3 will investigate the role of p38? in alcohol-induced tumor aggressiveness in animal models. The study will not only explore the basic cell biology of breast cancer aggressiveness, but also elucidate the mechanisms of alcohol's tumor promotion action. The outcomes will help developing new therapeutic strategy for breast cancer treatment and alcohol-mediated tumor promotion.

Public Health Relevance

Excessive alcohol consumption is associated with advanced and aggressive breast cancers, suggesting that alcohol may enhance mammary tumor progression and metastasis. We found that p38? signaling is down stream of ErbB2 and hypothesize that alcohol activates p38? which promotes tumor aggressiveness and accelerates mammary tumor development. This proposal will elucidate the mechanisms by which alcohol promotes the progression of mammary tumors and identify therapeutic targets for alcohol-associated tumor promotion.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA017226-07
Application #
8784433
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Jung, Kathy
Project Start
2008-03-05
Project End
2019-08-31
Budget Start
2014-09-05
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
$332,832
Indirect Cost
$107,832
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Liu, Dexiang; Ke, Zunji; Luo, Jia (2016) Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy. Mol Neurobiol :
Xu, Mei; Wang, Siying; Qi, Yuanlin et al. (2016) Role of MCP-1 in alcohol-induced aggressiveness of colorectal cancer cells. Mol Carcinog 55:1002-11
Xu, Mei; Ren, Zhenhua; Wang, Xin et al. (2016) ErbB2 and p38γ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis. Mol Cancer 15:52
Xu, Mei; Wang, Siying; Ren, Zhenhua et al. (2016) Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ. Oncotarget 7:3489-505
Ren, Zhenhua; Yang, Fanmuyi; Wang, Xin et al. (2016) Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation. Toxicol Appl Pharmacol 308:11-9
Yang, Fanmuyi; Luo, Jia (2015) Endoplasmic Reticulum Stress and Ethanol Neurotoxicity. Biomolecules 5:2538-53
Wang, Fei; Yang, Jin-Lian; Yu, Ke-ke et al. (2015) Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma. Mol Cancer 14:10
Wang, Haiping; Wang, Xin; Ke, Zun-Ji et al. (2015) Tunicamycin-induced unfolded protein response in the developing mouse brain. Toxicol Appl Pharmacol 283:157-67
Baldwin, Lauren A; Hoff, John T; Lefringhouse, Jason et al. (2014) CD151-α3β1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling. Oncotarget 5:12203-17
Lu, Yanmin; Ni, Fang; Xu, Mei et al. (2014) Alcohol promotes mammary tumor growth through activation of VEGF-dependent tumor angiogenesis. Oncol Lett 8:673-678

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