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Transcript-specific differences in m6A modifications in endocrine-sensitive and resistant breast cancer cells II

ABSTRACT: Acquired resistance to endocrine therapies (ET) remains a clinical problem for breast cancer patients whose initial tumors express estrogen receptor α (ER). Epigenetic changes are among the mechanisms involved in the development of ET resistance. We tested the hypothesis that the epitranscriptomic modification N-6 methyladenosine (m6A) differentially regulates the abundance of mRNA transcripts in ET-sensitive MCF-7 versus LCC9 ET-resistant ER+ human breast cancer cells. Direct mRNA sequencing (dRNA-seq) was performed on five replicates for each cell line +/- treatment with 100 nM 4-hydroxytamoxifen (4-OHT) using Nanopore MinION long read RNA-seq. Parallel short read Illumina RNA-seq was used to quantify differential transcript abundance. Statistical analysis integrated m6Anet, a machine-learning algorithm designed to call m6A modified bases, with a generalized linear model following a binomial distribution analysis to identify significant differential m6A modification ratios (DMR). Our findings reveal distinct m6A modification patterns in ET-resistant LCC9 breast cancer cells and in response to 4-OHT treatment compared to their ET-sensitive parental MCF-7 cells, suggesting a potential role for epitranscriptomic alterations in the development of ET resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269294 | GEO | 2025/07/16

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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Transcript-specific differences in m6A modifications in endocrine-sensitive and resistant breast cancer cells II

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