Modelling the MYC-driven normal-to-tumour switch in breast cancer

The potent MYC oncoprotein is deregulated in many human cancers, including breast carcinoma, and is associated with aggressive disease. To understand the mechanisms and vulnerabilities of MYC-driven breast cancer, we have generated an model that mimics human disease in response to MYC deregulation....

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Bibliographic Details
Published in:Disease models & mechanisms 2019-07, Vol.12 (7)
Main Authors: Lourenco, Corey, Kalkat, Manpreet, Houlahan, Kathleen E, De Melo, Jason, Longo, Joseph, Done, Susan J, Boutros, Paul C, Penn, Linda Z
Format: Article
Language:English
Subjects:
Breast - metabolism
Breast - pathology
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer model
Cell cycle
Cell Line, Tumor
Cell Transformation, Neoplastic - genetics
Driver oncogene
Female
Gene Expression Regulation, Neoplastic
Genes, myc
Genetic engineering
Genomes
Humans
Kinases
Lymphoma
Microenvironment
Models, Biological
MYC
Neoplasm Invasiveness
Phosphatidylinositol 3-Kinases - metabolism
PI3K
Proteins
Signal Transduction
Tumors
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Summary:The potent MYC oncoprotein is deregulated in many human cancers, including breast carcinoma, and is associated with aggressive disease. To understand the mechanisms and vulnerabilities of MYC-driven breast cancer, we have generated an model that mimics human disease in response to MYC deregulation. MCF10A cells ectopically expressing a common breast cancer mutation in the phosphoinositide 3 kinase pathway (PIK3CA ) led to the development of organised acinar structures in mice. Expressing both PIK3CA and deregulated MYC led to the development of invasive ductal carcinoma. Therefore, the deregulation of MYC expression in this setting creates a MYC-dependent normal-to-tumour switch that can be measured These MYC-driven tumours exhibit classic hallmarks of human breast cancer at both the pathological and molecular level. Moreover, tumour growth is dependent upon sustained deregulated MYC expression, further demonstrating addiction to this potent oncogene and regulator of gene transcription. We therefore provide a MYC-dependent model of breast cancer, which can be used to assay tumour signalling pathways, proliferation and transformation from normal breast acini to invasive breast carcinoma. We anticipate that this novel MYC-driven transformation model will be a useful research tool to better understand the oncogenic function of MYC and for the identification of therapeutic vulnerabilities.
ISSN:1754-8403
1754-8411
DOI:10.1242/dmm.038083