دورية أكاديمية
أعرض في EDS

MLL3 is a de novo cause of endocrine therapy resistance.

التفاصيل البيبلوغرافية
العنوان: MLL3 is a de novo cause of endocrine therapy resistance.
المؤلفون: Stauffer KM; Vanderbilt University, Nashville, Tennessee, USA., Elion DL; Vanderbilt University, Nashville, Tennessee, USA., Cook RS; Vanderbilt University, Nashville, Tennessee, USA., Stricker T; Vanderbilt University, Nashville, Tennessee, USA.
المصدر: Cancer medicine [Cancer Med] 2021 Nov; Vol. 10 (21), pp. 7692-7711. Date of Electronic Publication: 2021 Sep 28.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: John Wiley & Sons Ltd Country of Publication: United States NLM ID: 101595310 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2045-7634 (Electronic) Linking ISSN: 20457634 NLM ISO Abbreviation: Cancer Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Malden, MA] : John Wiley & Sons Ltd., c2012-
مواضيع طبية MeSH: Gene Expression Regulation, Neoplastic* , Mutation*, Antineoplastic Agents, Hormonal/*therapeutic use , Breast Neoplasms/*drug therapy , Breast Neoplasms/*genetics , DNA-Binding Proteins/*genetics , Drug Resistance, Neoplasm/*genetics, Binding Sites ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Estrogen Receptor alpha/metabolism ; Female ; Fulvestrant/therapeutic use ; Humans ; Tamoxifen/therapeutic use
مستخلص: Background: Cancer resequencing studies have revealed epigenetic enzymes as common targets for recurrent mutations. The monomethyltransferase MLL3 is among the most recurrently mutated enzymes in ER+ breast cancer. The H3K4me1 marks created by MLL3 can define enhancers. In ER+ breast cancer, ERα genome-binding sites are primarily distal enhancers. Thus, we hypothesize that mutation of MLL3 will alter the genomic binding and transcriptional regulatory activity of ERα.
Methods: We investigated the genomic consequences of knocking down MLL3 in an MLL3/PIK3CA WT ER+ breast cancer cell line.
Results: Loss of MLL3 led to a large loss of H3K4me1 across the genome, and a shift in genomic location of ERα-binding sites, which was accompanied by a re-organization of the breast cancer transcriptome. Gene set enrichment analyses of ERα-binding sites in MLL3 KD identified endocrine therapy resistance terms, and we showed that MLL3 KD cells are resistant to tamoxifen and fulvestrant. Many differentially expressed genes are controlled by the small collection of new locations of H3K4me1 deposition and ERα binding, suggesting that loss of functional MLL3 leads to new transcriptional regulation of essential genes. Motif analysis of RNA-seq and ChIP-seq data highlighted SP1 as a critical transcription factor in the MLL3 KD cells. Differentially expressed genes that display a loss of ERα binding upon MLL3 KD also harbor increased SP1 binding.
Conclusions: Our data show that a decrease in functional MLL3 leads to endocrine therapy resistance. This highlights the importance of genotyping patient tumor samples for MLL3 mutation upon initial resection, prior to deciding upon treatment plans.
(© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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معلومات مُعتمدة: K08 CA148912 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: MLL3 protein; breast neoplasms; epigenetics; estrogen receptor alpha; genomics
المشرفين على المادة: 0 (Antineoplastic Agents, Hormonal)
0 (DNA-Binding Proteins)
0 (Estrogen Receptor alpha)
0 (KMT2C protein, human)
094ZI81Y45 (Tamoxifen)
22X328QOC4 (Fulvestrant)
تواريخ الأحداث: Date Created: 20210928 Date Completed: 20220317 Latest Revision: 20220317
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8559462
DOI: 10.1002/cam4.4285
PMID: 34581028
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-7634
DOI:10.1002/cam4.4285