Time resolved gene expression analysis during tamoxifen adaption of MCF-7 cells identifies long non-coding RNAs with prognostic impact.
Martin PorschEsra ÖzdemirMartin WisniewskiSebastian GrafFabian BullKatrin HoffmannAtanas IgnatovJohannes HaybaeckIvo GrosseThomas KalinskiNorbert NassPublished in: RNA biology (2019)
Acquired tamoxifen resistance is a persistent problem for the treatment of estrogen receptor positive, premenopausal breast cancer patients and predictive biomarkers are still elusive. We here analyzed gene expression changes in a cellular model to identify early and late changes upon tamoxifen exposure and thereby novel prognostic biomarkers. Estrogen receptor positive MCF-7 cells were incubated with 4OH-tamoxifen (10 nM) and gene expression analyzed by array hybridization during 12 weeks. Array results were confirmed by nCounter- and qRT-PCR technique. Pathway enrichment analysis revealed that early responses concerned mainly amine synthesis and NRF2-related signaling and evolved into a stable gene expression pattern within 4 weeks characterized by changes in glucuronidation-, estrogen metabolism-, nuclear receptor- and interferon signaling pathways. As a large number of long non coding RNAs was subject to regulation, we investigated 5 of these (linc01213, linc00632 linc0992, LOC101929547 and XR_133213) in more detail. From these, only linc01213 was upregulated but all were less abundant in estrogen-receptor negative cell lines (MDA-MB 231, SKBR-3 and UACC3199). In a web-based survival analysis linc01213 and linc00632 turned out to have prognostic impact. Linc01213 was investigated further by plasmid-mediated over-expression as well as siRNA down-regulation in MCF-7 cells. Nevertheless, this had no effect on proliferation or expression of tamoxifen regulated genes, but migration was increased. In conclusion, the cellular model identified a set of lincRNAs with prognostic relevance for breast cancer. One of these, linc01213 although regulated by 4OH-tamoxifen, is not a central regulator of tamoxifen adaption, but interferes with the regulation of migration.
Keyphrases
- estrogen receptor
- long non coding rna
- poor prognosis
- gene expression
- induced apoptosis
- breast cancer cells
- cell cycle arrest
- dna methylation
- signaling pathway
- long noncoding rna
- cell proliferation
- genome wide
- oxidative stress
- endoplasmic reticulum stress
- escherichia coli
- transcription factor
- cell death
- binding protein
- pi k akt
- immune response
- dendritic cells
- drug delivery
- single cell
- mass spectrometry
- atomic force microscopy
- postmenopausal women
- preterm birth
- photodynamic therapy
- drug induced
- combination therapy