Abstract
ABSTRACTThe 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 in vivo 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 (PIK3CAH1047R) led to the development of organised acinar structures in mice. Expressing both PIK3CAH1047R 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 in vivo. 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 in vivo 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.
Highlights
MYC deregulation occurs in the majority of human cancers and is an ideal therapeutic target (Kalkat et al, 2017)
In vivo transformation of MCF10A cells is dependent on active PI3K signalling, deregulated MYC and the presence of MYC Box II We chose to model breast cancer as MYC is often deregulated and contributes to the progression of this disease (Singhi et al, 2011; Stratikopoulos et al, 2015)
PIK3CA is mutated in approximately 30% of breast cancer patient tumours, whereas MYC deregulation, primarily scored through amplification, occurs in approximately 20% of breast cancers (Chen and Olopade, 2008; Nik-Zainal et al, 2016)
Summary
MYC deregulation occurs in the majority of human cancers and is an ideal therapeutic target (Kalkat et al, 2017). Most cancer cell line models do not accurately reflect human tumours in vivo, are derived from already fully transformed tumour tissue, and are not necessarily driven by or dependent on deregulated MYC.
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