International Journal of Molecular Sciences

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Dear Colleagues,

Hormone-sensitive cancers are influenced by a variety of events, including hormonal, genetic, and environmental factors. Specifically, dysregulation of the steroidogenic machinery, involving sex steroid hormones, has long been linked to the pathogenesis of a variety of hormone-sensitive malignancies, including breast, prostrate, and gynecological cancers. Despite recent advances in genetic and proteomic landscapes detailing regulatory insights into various relevant cancers, mortality rates remain very high globally. An early diagnosis of any of these cancers can significantly reduce morbidity and psychological distress, and possibly even save the life in certain cases, in patients afflicted with the indicated aggressive malignant diseases. In-depth understanding of tumor microenvironment, heterogeneity and signaling pathways, utilizing/analyzing pertinent cell lines, primary tumors, and bioinformatics, along with genomic and molecular profiles, would be valuable for establishing novel biomarker(s) revealing diagnosis and staging of different cancer types. While considerable challenges exist for development of a therapeutic target for the specific cancer type mentioned, accumulating evidence indicates that histone deacetylase (HDAC) inhibitors, by targeting multiple aspects, display favorable outcomes in a number of these hormone-dependent cancers, since dysregulation of HDACs is primary event in tumorigenesis. Under these circumstances, discovery of novel agents effective for diagnostic, preventive, and therapeutic purposes should be the major focus for combating various hormone-sensitive cancers.

This Special Issue provides a venue for publishing both original research and review articles that enhance improved understanding of therapeutic strategies facilitating diagnosis and treatment for any hormone-dependent cancer.

Dr. Pulak R. Manna
Guest Editor

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Keywords

hormone-sensitive cancers
hormone dysregulation
steroid hormones
mechanistic insights
signaling crosstalk
oncogenic events
epigenetics
tumor suppressor genes
bioinformatics
endocrine pathophysiology
signaling pathways
anticancer agents
therapeutic strategies
aging and cancers

Published Papers (2 papers)

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Research

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19 pages, 4409 KiB

Open AccessArticle

Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics

by Pulak R. Manna, Shengping Yang and P. Hemachandra Reddy

Int. J. Mol. Sci. 2023, 24(22), 16488; https://doi.org/10.3390/ijms242216488 - 18 Nov 2023

Viewed by 1304

Abstract

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. Full article

(This article belongs to the Special Issue Hormone-Sensitve Cancers: Pathogenesis and Therapeutics)

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Review

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15 pages, 1018 KiB

Open AccessReview

Metastatic ER+ Breast Cancer: Mechanisms of Resistance and Future Therapeutic Approaches

by Farah Raheem, Suganya Arunachalam Karikalan, Felipe Batalini, Aya El Masry and Lida Mina

Int. J. Mol. Sci. 2023, 24(22), 16198; https://doi.org/10.3390/ijms242216198 - 11 Nov 2023

Cited by 3 | Viewed by 2655

Abstract

Endocrine therapy is the main treatment for hormone receptor-positive (HR+) breast cancer. However, advanced tumors develop resistance to endocrine therapy, rendering it ineffective as the disease progresses. There are several molecular mechanisms of primary and secondary endocrine resistance. Resistance can develop due to either alteration of the estrogen receptor pathway (e.g., ESR1 mutations) or upstream growth factors signaling pathways (e.g., PI3K/Akt/mTOR pathway). Despite progress in the development of molecularly targeted anticancer therapies, the emergence of resistance remains a major limitation and an area of unmet need. In this article, we review the mechanisms of acquired endocrine resistance in HR+ advanced breast cancer and discuss current and future investigational therapeutic approaches. Full article

(This article belongs to the Special Issue Hormone-Sensitve Cancers: Pathogenesis and Therapeutics)

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