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The cellular response of immortalized TRF2dB fibroblast cells by 4-hydroxytamoxifen drug treatments

ABSTRACT: In our study, we have successfully generated a cell line that stably expresses a mutant TRF2 with a truncated N-terminal basic domain from BJ normal human fibroblasts. This mutant named, TRF2∆B, can artificially loop out telomeric DNA as ECTR in circular forms, mediated by XRCC3 holiday junction resolution protein and SLX4 associated recombination endonucleases. To avoid the deleterious effect on cell growth resulting from constant TRF2∆B expression, we fused TRF2ΔB with an estrogen receptor ligand-binding domain variant ERT2 to keep TRF2∆B inactive in the BJTL cells, and in the presence of 4-hydroxytamoxifen (4-OHT),which binds to ERT2, TRF2∆B becomes active. With this system, we aim to investigate the cellular response of immortalized BJ fibroblast cells to 4-OHT drug treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86274 | GEO | 2016/09/01

SECONDARY ACCESSION(S): PRJNA341341

REPOSITORIES: GEO

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Project description:MCF-7:PF is a a new in vitro model of antihormone resistant breast cancer that exhibits the characteristics of acquired tamoxifen resistance in vivo. It is well known that estrogen (E2) induces apoptosis in long-term estrogen-deprived breast cancer cells, MCF-7:5C (PubMed References PMID:15862958, PMID:16333030). MCF-7:PF was derived from MCF-7:5C through inhibition of c-Src, which blocks E2-induced apoptosis, coverts E2 responses from apoptosis to proliferation. MCF-7:PF cell growth is stimulated by E2 and SERMS in an ERα-dependent manner. Abstract: A c-Src inhibitor blocks estrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to stimulating growth in E2-deprived breast cancer cells. A resulting cell line, MCF-7:PF, is reprogrammed with features of functional estrogen receptor (ER) and over-expression of insulin-like growth factor-1 receptor beta (IGF-1Rβ). We addressed the question of whether the antiestrogenic selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Unexpectedly, 4-OHT stimulated cell growth in an ER-dependent manner. However, unlike E2, 4-OHT suppressed classic ER-target genes as does the pure antiestrogen ICI 182,780, even during growth stimulation. Chromatin-immunoprecipitation (ChIP) assay indicated that 4-OHT did not recruit ER or nuclear receptor coactivator 3 (SRC3) to the promoter of ER-target gene, pS2. Paradoxically, 4-OHT reduced total IGF-1Rβ but increased phosphorylation of IGF-1Rβ, which was responsible for the activation of the phosphatidylinositol-3 kinases (PI3K)/Akt signaling pathway. Mechanistic studies revealed that 4-OHT rapidly activated the non-genomic pathway through ER, but other membrane-associated proteins such as IGF-1Rβ and c-Src participated. Furthermore, 4-OHT was more potent than E2 to up-regulate membrane remodeling molecules and activated focal adhesion molecules to promote cell growth. Therefore, disruption of membrane-associated signaling completely abolished 4-OHT-stimulated cell growth, but not E2-stimulated cell growth. Despite continued suppression of classic ER-target genes, 4-OHT activated the complex network of cytoskeleton remodeling and extracellular matrix-related signaling which facilitated 4-OHT-stimulated cell growth. This study is the first to recapitulate a cellular model in vitro of acquired tamoxifen (TAM) resistance developed in athymic mice in vivo.

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The cellular response of immortalized TRF2dB fibroblast cells by 4-hydroxytamoxifen drug treatments

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