Part of: Cancer Cell Line Encyclopedia (CCLE) project.
Part of: ENCODE project common cell types; tier 2.
Part of: JFCR39 cancer cell line panel.
Part of: JFCR45 cancer cell line panel.
Part of: ICBP43 breast cancer cell line panel.
Part of: KuDOS 95 cell line panel.
Part of: MD Anderson Cell Lines Project.
Part of: NCI60 cancer cell line panel.
Registration: Chiron Master Culture Collection; CMCC 10377 (CMCC #10377).
Doubling time: 1.8 days (PubMed=9671407); 80 hours (PubMed=25984343); 31.2 hours (PubMed=22628656); 25.4 hours (NCI-DTP); ~50 hours, with a range of 30-72 hours (DSMZ).
Microsatellite instability: Stable (MSS) (PubMed=12661003; PubMed=23671654; Sanger).
Omics: Array-based CGH.
Omics: CNV analysis.
Omics: Deep antibody staining analysis.
Omics: Deep exome analysis.
Omics: Deep phosphoproteome analysis.
Omics: Deep proteome analysis.
Omics: Deep RNAseq analysis.
Omics: DNA methylation analysis.
Omics: Fluorescence phenotype profiling.
Omics: H3K4me3 ChIP-seq epigenome analysis.
Omics: lncRNA expression profiling.
Omics: Metabolome analysis.
Omics: miRNA expression profiling.
Omics: N-glycan profiling.
Omics: Protein expression by reverse-phase protein arrays.
Omics: shRNA library screening.
Omics: SNP array analysis.
Omics: Transcriptome analysis.
Omics: Virome analysis using proteomics.
Anecdotal: This is the first hormone-responsive breast cancer cell line to have been established.
Anecdotal: Helen Mallon (sister Catherine Frances), the patient from which this cell line is derived was a nun (Sister Catherine Frances) at the Immaculate Heart of Mary Convent in Monroe, Michigan.
Misspelling: 'MFC-7'in ChEMBL CHEMBL614345 and CHEMBL3307491.
Discontinued: ATCC; CRL-12584.
Discontinued: JCRB; NIHS0200.
Derived from metastatic site: Pleural effusion.
TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53β promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53β increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53β is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53β depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53β induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression.
The target of rapamycin (TOR) protein kinase forms multi-subunit TOR complex 1 (TORC1) and TOR complex 2 (TORC2), which exhibit distinct substrate specificities. Sin1 is one of the TORC2-specific subunit essential for phosphorylation and activation of certain AGC-family kinases. Here, we show that Sin1 is dispensable for the catalytic activity of TORC2, but its conserved region in the middle (Sin1CRIM) forms a discrete domain that specifically binds the TORC2 substrate kinases. Sin1CRIM fused to a different TORC2 subunit can recruit the TORC2 substrate Gad8 for phosphorylation even in the sin1 null mutant of fission yeast. The solution structure of Sin1CRIM shows a ubiquitin-like fold with a characteristic acidic loop, which is essential for interaction with the TORC2 substrates. The specific substrate-recognition function is conserved in human Sin1CRIM, which may represent a potential target for novel anticancer drugs that prevent activation of the mTORC2 substrates such as AKT.
TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.
The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs). Strikingly, many DSBs that accumulate in response to E2 are R-loop dependent. Thus, R-loops resulting from the E2 transcriptional response are a significant source of DNA damage. This work reveals a novel mechanism by which E2 stimulation leads to genomic instability and highlights how transcriptional programs play an important role in shaping the genomic landscape of DNA damage susceptibility.
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