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Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics
Breast cancer (BC) is a heterogeneous condition and comprises molecularly distinct subtypes. An imbalance in the levels of epigenetic histone deacetylases (HDACs), modulating estrogen accumulation, especially 17β-estradiol (E2), promotes breast tumorigenesis. In the present study, analyses of The Ca...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671690/ https://www.ncbi.nlm.nih.gov/pubmed/38003678 http://dx.doi.org/10.3390/ijms242216488 |
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author | Manna, Pulak R. Yang, Shengping Reddy, P. Hemachandra |
author_facet | Manna, Pulak R. Yang, Shengping Reddy, P. Hemachandra |
author_sort | Manna, Pulak R. |
collection | PubMed |
description | Breast cancer (BC) is a heterogeneous condition and comprises molecularly distinct subtypes. An imbalance in the levels of epigenetic histone deacetylases (HDACs), modulating estrogen accumulation, especially 17β-estradiol (E2), promotes breast tumorigenesis. In the present study, analyses of The Cancer Genome Atlas (TCGA) pan-cancer normalized RNA-Seq datasets revealed the dysregulation of 16 epigenetic enzymes (among a total of 18 members) in luminal BC subtypes, in comparison to their non-cancerous counterparts. Explicitly, genomic profiling of these epigenetic enzymes displayed increases in HDAC1, 2, 8, 10, 11, and Sirtuins (SIRTs) 6 and 7, and decreases in HDAC4–7, –9, and SIRT1–4 levels, respectively, in TCGA breast tumors. Kaplan–Meier plot analyses showed that these HDACs, with the exception of HDAC2 and SIRT2, were not correlated with the overall survival of BC patients. Additionally, disruption of the epigenetic signaling in TCGA BC subtypes, as assessed using both heatmaps and boxplots, was associated with the genomic expression of factors that are instrumental for cholesterol trafficking/utilization for accelerating estrogen/E2 levels, in which steroidogenic acute regulatory protein (STAR) mediates the rate-limiting step in steroid biosynthesis. TCGA breast samples showed diverse expression patterns of a variety of key steroidogenic markers and hormone receptors, including LIPE, CYP27A1, STAR, STARD3, CYP11A1, CYP19A1, ER, PGR, and ERBB2. Moreover, regulation of STAR-governed steroidogenic machinery was found to be influenced by various transcription factors, i.e., CREB1, CREM, SF1, NR4A1, CEBPB, SREBF1, SREBF2, SP1, FOS, JUN, NR0B1, and YY1. Along these lines, ingenuity pathway analysis (IPA) recognized a number of new targets and downstream effectors influencing BCs. Of note, genomic, epigenomic, transcriptional, and hormonal anomalies observed in human primary breast tumors were qualitatively similar in pertinent BC cell lines. These findings identify the functional correlation between dysregulated epigenetic enzymes and estrogen/E2 accumulation in human breast tumors, providing the molecular insights into more targeted therapeutic approaches involving the inhibition of HDACs for combating this life-threatening disease. |
format | Online Article Text |
id | pubmed-10671690 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106716902023-11-18 Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics Manna, Pulak R. Yang, Shengping Reddy, P. Hemachandra Int J Mol Sci Article Breast cancer (BC) is a heterogeneous condition and comprises molecularly distinct subtypes. An imbalance in the levels of epigenetic histone deacetylases (HDACs), modulating estrogen accumulation, especially 17β-estradiol (E2), promotes breast tumorigenesis. In the present study, analyses of The Cancer Genome Atlas (TCGA) pan-cancer normalized RNA-Seq datasets revealed the dysregulation of 16 epigenetic enzymes (among a total of 18 members) in luminal BC subtypes, in comparison to their non-cancerous counterparts. Explicitly, genomic profiling of these epigenetic enzymes displayed increases in HDAC1, 2, 8, 10, 11, and Sirtuins (SIRTs) 6 and 7, and decreases in HDAC4–7, –9, and SIRT1–4 levels, respectively, in TCGA breast tumors. Kaplan–Meier plot analyses showed that these HDACs, with the exception of HDAC2 and SIRT2, were not correlated with the overall survival of BC patients. Additionally, disruption of the epigenetic signaling in TCGA BC subtypes, as assessed using both heatmaps and boxplots, was associated with the genomic expression of factors that are instrumental for cholesterol trafficking/utilization for accelerating estrogen/E2 levels, in which steroidogenic acute regulatory protein (STAR) mediates the rate-limiting step in steroid biosynthesis. TCGA breast samples showed diverse expression patterns of a variety of key steroidogenic markers and hormone receptors, including LIPE, CYP27A1, STAR, STARD3, CYP11A1, CYP19A1, ER, PGR, and ERBB2. Moreover, regulation of STAR-governed steroidogenic machinery was found to be influenced by various transcription factors, i.e., CREB1, CREM, SF1, NR4A1, CEBPB, SREBF1, SREBF2, SP1, FOS, JUN, NR0B1, and YY1. Along these lines, ingenuity pathway analysis (IPA) recognized a number of new targets and downstream effectors influencing BCs. Of note, genomic, epigenomic, transcriptional, and hormonal anomalies observed in human primary breast tumors were qualitatively similar in pertinent BC cell lines. These findings identify the functional correlation between dysregulated epigenetic enzymes and estrogen/E2 accumulation in human breast tumors, providing the molecular insights into more targeted therapeutic approaches involving the inhibition of HDACs for combating this life-threatening disease. MDPI 2023-11-18 /pmc/articles/PMC10671690/ /pubmed/38003678 http://dx.doi.org/10.3390/ijms242216488 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Manna, Pulak R. Yang, Shengping Reddy, P. Hemachandra Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics |
title | Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics |
title_full | Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics |
title_fullStr | Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics |
title_full_unstemmed | Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics |
title_short | Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics |
title_sort | epigenetic dysregulation and its correlation with the steroidogenic machinery impacting breast pathogenesis: data mining and molecular insights into therapeutics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671690/ https://www.ncbi.nlm.nih.gov/pubmed/38003678 http://dx.doi.org/10.3390/ijms242216488 |
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