c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer.
The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer.
Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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Nair
Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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Roden
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
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WS
Teo
Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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McFarland
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
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Junankar
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
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Ye
Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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Nguyen
Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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J
Yang
Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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Nikolic
Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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M
Hui
1] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia [2] Department of Anatomical Pathology, Sydpath, St Vincent's Hospital, Darlinghurst, NSW, Australia.
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Morey
School of Medical Sciences, University of New South Wales, Camperdown, NSW, Australia.
J
J
Shah
1] Department of Pathology and Laboratory Medicine, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
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Pfefferle
1] Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA [2] Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
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Usary
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
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Selinger
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] School of Biotechnology and Biomolecular Sciences, University of New South Wales, NSW, Australia.
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Baker
School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia.
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Armstrong
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
M J
MJ
Cowley
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia [3] Discipline of Physiology and Bosch Institute, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
M J
MJ
Naylor
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
C J
CJ
Ormandy
The University of Queensland, UQ Centre for Clinical Research, School of Medicine and Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD, Australia.
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Lakhani
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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JI
Herschkowitz
1] Department of Pathology and Laboratory Medicine, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA [3] Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
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Perou
1] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia [2] Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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Kaplan
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia [3] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia [4] Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
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O'Toole
1] Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
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Swarbrick
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008875:Middle Aged; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D016019:Survival Analysis; D059467:Transcriptome; D055815:Young Adult
D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; C489427:MYC protein, human; C508053:ERBB2 protein, human