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Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer and nominates c-Met and TRIM24 as therapeutic targets

ABSTRACT: Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature revealed strong correlation with human MpBC tumors and MpBC xenograft (PDX) models. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC PDX tumorspheres revealed the therapeutic potential of targeting TRIM24. Altogether, global expression, single-cell immunophenotyping and mechanistic studies of tumors and MpBC PDX nominated TRIM24-activated c-MET/PI3K/mTOR pathways and TRIM24, which were validated as potential MpBC therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165407 | GEO | 2021/06/25

REPOSITORIES: GEO

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Project description:Recent genetic studies in mice have established a key role for the nuclear receptor coregulator Trim24 in liver tumor suppression and provided evidence that Trim24 suppresses hepatocarcinogenesis by inhibiting retinoic acid receptor alpha (Rara)-dependent transcription and cell proliferation. However, it is unknown which downstream targets of Rara regulated by Trim24 are critical for tumorigenesis. We report here that loss of Trim24 results in the overexpression of interferon (IFN)/STAT pathway genes in the liver, a process that occurs early in tumorigenesis and is more pronounced in tumors, despite the enhanced expression, late in the disease, of negative regulators such as Usp18, Socs1 and Socs2. Remarkably, Rara haplodeficiency, which was previously shown to suppress tumor development in Trim24-/- mice, also suppresses overexpression of the IFN/STAT pathway, thus providing evidence for a cross-pathway control that may be relevant to the transformation process. Biochemical studies revealed that Trim24 binds to the retinoic acid (RA)-responsive element in the Stat1 promoter in a RA-dependent manner and represses RA-induced transcription from this promoter. Together, these results identify Trim24 as a novel regulator of the IFN/STAT pathway and indicate that Trim24-mediated repression of the IFN/STAT signaling through Rara inhibition may play a critical role in preventing liver cancer. Generation of Trim24-/- mice has been described previously (Khetchoumian et al., 2007) by gene disruption. To generate compound mutant mice with a single allele of Rara deleted in the Trim24 -/- mutant background, we crossed Trim24 -/- mice with Rara+/- mice. The resulting Trim24+/- Rara+/- mice were generated in the hybrid (C57BL/6 (60%), 129/Sv (40%)) genetic background. These double heterozygous Trim24+/- Rara+/- mice were intercrossed to generate Trim24 -/-, Trim24 -/- Rara+/- and wild-type mice. Transcriptional profiling of mice at 5-weeks and 14-weeks of age.

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Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer and nominates c-Met and TRIM24 as therapeutic targets

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