Soleimani Dodaran, M. | bioRxiv Science

bioRxiv2020

Time-resolved profiling reveals ATF3 as a novel mediator of endocrine resistance in breast cancer

Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express Estrogen Receptor (ER) account for around 70% of cases and are mostly treated with targeted endocrine therapy. However, 40% of these tumors eventually relapse due to resistance development and further treatment of these patients is highly ineffective. In this study we profiled the early phases of the resistance development process to uncover drivers of this phenomenon. Time-resolved analysis revealed that ATF3, a member of the ATF/CREB family of transcription factors, acts as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. ATF3 was found to be essential in controlling crucial processes such as proliferation, cell cycle and apoptosis during the early response to treatment through the regulation of MAPK/AKT signaling pathways. Its essential role was confirmed in vivo in a mouse model and elevated expression of ATF3 was verified in patient datasets, adding clinical relevance to our findings. This study proposes ATF3 as a novel mediator of endocrine resistance development in breast cancer and elucidates its role in the regulation of downstream pathways activities.

cancer biology↗

bioRxiv2019

Candidate methylation sites associated with endocrine therapy resistance in the TCGA ER+/HER2- breast cancer cohort

BackgroundEstrogen receptor (ER) positive breast cancer is often effectively treated with drugs that inhibit ER signaling, i.e., tamoxifen (TAM) and aromatase inhibitors (AIs). However, about 30% of ER+ breast cancer patients develop resistance to therapy leading to tumour recurrence. Changes in the methylation profile have been implicated as one of the mechanisms through which therapy resistance develops. Therefore, we aimed to identify methylation loci associated with endocrine therapy resistance. MethodsWe used genome-wide DNA methylation profiles of primary ER+ tumors from The Cancer Genome Atlas in combination with curated data on survival and treatment to predict development of endocrine resistance. Association of individual DNA methylation markers with survival was assessed using Cox proportional hazards models in a cohort of ER+/HER2- tumours (N=552) and two sub-cohorts corresponding to the endocrine treatment (AIs or TAM) that patients received (N=210 and N=172, respectively). Models were adjusted for clinical variables tumour stage, age, AI treatment and luminal subtype. We also identified signatures of multiple methylation loci associated with survival using Cox proportional hazards models with elastic net regularization. Individual markers and multivariable signatures were compared with DNA methylation profiles generated in a time course experiment using the T47D ER+ breast cancer cell line treated with tamoxifen or deprived from estrogen. ResultsWe identified 132, 9 and 1 CpGs for which DNA methylation is significantly associated with survival in the ER+/HER2-, TAM and AI cohorts respectively. Corresponding multi-locus signatures consisted of 171, 50 and 160 CpGs and showed a large overlap with the corresponding single-locus signatures. Single-locus signatures for the ER+/HER2- and TAM cohorts were conserved among the loci that were differentially methylated in endocrine-resistant T47D cells. Similarly, multi-locus signatures for the ER+/HER2- and AI cohorts were conserved in endocrine-resistant T47D cells. ConclusionsWe identified individual and multivariable DNA methylation markers associated with therapy resistance independently of luminal status. Our results suggest that these markers identified from primary tumours and prior to any endocrine treatment are associated with development of endocrine resistance.

bioinformatics↗