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Characterising transcriptional changes throughout c-MYC-driven tumorigenesis in the mammary gland (MMTV-cMYC mouse model)

ABSTRACT: c-MYC oncogene is one of the driver lesions in many types of cancer. Among breast cancers, triple negative subtype (TNBC) is characterised by high aggressivness and is associated with high transcriptional activity of MYC. MMTV-cMYC mouse model, in which ectopic expression of c-MYC is driven by mouse mammary tumour virus promoter, is a widely used model of MYC-driven breast cancer. MMTV-cMYC mice develop tumours in the mammary gland(s) at ages ranging from 6 to 10 months. MYC regulates activity of multiple processes including cell cyle, proliferation, metabolism, protein translation, inflammation and apoptosis among others. Previous studies demonstrated that MMTV-cMYC tumours are very heterogeneous. However, how different procecesses regulated by MYC contribute to different steps of the transformation process and tumour development is not known. To evaluate how the expression of genes changes from the initiation of transformation process by ectopic expression of c-MYC in mammary gland epithelial cells to the development of tumours, we perfomed RNAseq analysis of tissues collected from mammary glands and tumours of MMTV-cMYC mice of different ages. Wild type age-matched littermates were used as controls.

ORGANISM(S): Mus musculus

PROVIDER: GSE295796 | GEO | 2025/09/12

REPOSITORIES: GEO

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Project description:ErbB-2 overexpression and amplification occurs in 15 - 30% of human invasive breast carcinomas associated with poor clinical prognosis. Previously, we have demonstrated that four ErbB-2/Neu tyrosine-autophosphorylation sites within the cytoplasmic tail of the receptor recruit distinct adaptor proteins and are sufficient to mediate transforming signals in vitro. Two of these sites representing the Grb2 (Neu-YB) and Shc (Neu-YD) binding sites can induce mammary tumourigenesis and metastasis. Here we show that Neu-YC and Neu-YE transgenic mice develop metastatic mammary tumours. A detailed comparison of pathological and transcriptional profiles among all Neu mutant mouse models revealed that Neu-YC, -YD and -YE mammary tumours shared similar pathological and transcriptional features correlating with their capacity to signal through a common adaptor like Shc. In contrast, the Neu-YB mouse model displayed a unique pathology with a high metastatic potential that correlates with a distinct transcriptional profile. We identified genes specifically expressed in YB-induced mammary tumours, including CXCL12/SDF-1Î± that promotes malignant tumour progression. Furthermore, Neu-YB tumour epithelial cells showed abundant intracellular CXCL12/SDF-1Î± protein, which may reflect the more aggressive phenotype among all Neu mutant mouse models. These findings indicate that activation of distinct Neu-coupled signalling pathways has a deep impact on the biological behaviour of Neu-induced tumours. Experiment Overall Design: Total RNA was isolated from 10 individual flash frozen mammary tumour samples derived from our MMTV/neundl-NYPD, -YB, -YC, -YD, -YE and the parental MMTV/neu NDL2-5 strains. Two RNA pools, containing equal amount of total RNA from five individual tumours, were generated from each strain and functioned as a biological repeat. Five hundred nanograms of total RNA from each pool was subjected to one round of T7 linear amplification using the Amino Allyl MessageAmpTM aRNA Kit (Ambion, Austin, Texas). Ten micrograms of the resulting aRNA was labelled with Cy3 and Cy5 dyes. Each of the 12 Samples represents a dyeswap pair.

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Characterising transcriptional changes throughout c-MYC-driven tumorigenesis in the mammary gland (MMTV-cMYC mouse model)

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