Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors.
High-grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirm that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through the activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into the examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting.
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
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SI
Labidi-Galy
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
A
A
Clauss
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Ng
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
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Duraisamy
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA [3] Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA, USA.
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Elias
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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HY
Piao
The Cancer Institute of New Jersey, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA.
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Bilal
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
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Davidowitz
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Lu
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
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Badalian-Very
Research Laboratory of Pediatrics and Nephrology, Hungarian Academy of Sciences, Budapest, Hungary.
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Györffy
1] Harvard Medical School, Boston, MA, USA [2] Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.
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UB
Kang
1] Harvard Medical School, Boston, MA, USA [2] Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.
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Ficarro
The Cancer Institute of New Jersey, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA.
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Ganesan
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Mills
1] Harvard Medical School, Boston, MA, USA [2] Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.
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JA
Marto
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA [3] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
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Drapkin
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053492:Elafin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System / Q000235:genetics; D061986:MCF-7 Cells; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D040901:Proteomics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D053492:Elafin; D051020:bcl-X Protein