期刊
MOLECULAR CANCER THERAPEUTICS
卷 13, 期 12, 页码 3198-3209出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-14-0280
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资金
- IISc
- Department of Biotechnology, Government of India [BT/PR10536/MED/31/66/2009]
- Wellcome Trust/DBT India Alliance (IA) [500112/Z/09/Z]
- Department of Science and Technology
- DBT-IISc partnership programme
- University Grants Commission, Government of India
- Indian Council of Medical Research, Government of India
- Council of Scientific and Industrial Research, Government of India
- Prime Minister's Fellowship, Government of India
Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch-Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordinate hyperactivation of Notch1 and Ras/MAPK pathways in breast cancer patient specimens, as assessed by IHC for cleaved Notch1 and pErk1/2, respectively, correlated with early relapse to vital organs and poor overall survival. Interestingly, majority of such Notch1 (high)Erk(high) cases encompassed the highly aggressive triple-negative breast cancers (TNBC), and were enriched in stem cell markers. We further show that combinatorial inhibition of Notch1 and Ras/MAPK pathways, using a novel mAb against Notch1 and a MEK inhibitor, respectively, led to a significant reduction in proliferation and survival of breast cancer cells compared with individual inhibition. Combined inhibition also abrogated sphere-forming potential, and depleted the putative cancer stem-like cell subpopulation. Most importantly, combinatorial inhibition of Notch1 and Ras/MAPK pathways completely blocked tumor growth in a panel of breast cancer xenografts, including the TNBCs. Thus, our study identifies coordinate hyperactivation of Notch1 and Ras/MAPK pathways as novel biomarkers for poor breast cancer outcome. Furthermore, based on our preclinical data, we propose combinatorial targeting of these two pathways as a treatment strategy for highly aggressive breast cancers, particularly the TNBCs that currently lack any targeted therapeutic module. (C) 2014 AACR.
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