title: Coordinate hyperactivation of Notch1 and Ras/MAPK pathways correlates with poor patient survival: novel therapeutic strategy for aggressive breast cancers.
abstract: 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.
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.|Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India.
authors.forename: Suruchi
authors.initials: S
authors.lastname: Mittal
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Ankur
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Sai A
authors.initials: SA
authors.lastname: Balaji
authors.affiliation: Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India.
authors.forename: Manju C
authors.initials: MC
authors.lastname: Gowda
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Rajan R
authors.initials: RR
authors.lastname: Dighe
authors.affiliation: Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India.
authors.forename: Rekha V
authors.initials: RV
authors.lastname: Kumar
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Annapoorni
authors.initials: A
authors.lastname: Rangarajan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D016130:Immunophenotyping; D008207:Lymphatic Metastasis; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D047428:Protein Kinase Inhibitors; D051881:Receptor, Notch1; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins