Amyloid-ß and Phosphorylated Tau are the Key Biomarkers and Predictors of Alzheimer's Disease.

Alzheimer's disease (AD) is a age-related neurodegenerative disease and is a major public health concern both in Texas, US and Worldwide. This neurodegenerative disease is mainly characterized by amyloid-beta (Aß) and phosphorylated Tau (p-Tau) accumulation in the brains of patients with AD and increasing evidence suggests that these are key biomarkers in AD. Both Aß and p-tau can be detected through various imaging techniques (such as positron emission tomography, PET) and cerebrospinal fluid (CSF) analysis. The presence of these biomarkers in individuals, who are asymptomatic or have mild cognitive impairment can indicate an increased risk of developing AD in the future. Furthermore, the combination of Aß and p-tau biomarkers is often used for more accurate diagnosis and prediction of AD progression. Along with AD being a neurodegenerative disease, it is associated with other chronic conditions such as cardiovascular disease, obesity, depression, and diabetes because studies have shown that these comorbid conditions make people more vulnerable to AD. In the first part of this review, we discuss that biofluid-based biomarkers such as Aß, p-Tau in cerebrospinal fluid (CSF) and Aß & p-Tau in plasma could be used as an alternative sensitive technique to diagnose AD. In the second part, we discuss the underlying molecular mechanisms of chronic conditions linked with AD and how they affect the patients in clinical care.

Circulating Cell Free DNA and DNA Double-Strand Breakage in Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that is characterized by memory loss and multiple cognitive impairments. AD is pathologically characterized by age-dependent accumulation of amyloid-ß protein and the phosphorylation of tau protein in the brains of patients with AD. Clinically, manifestations of AD include cognitive decline, dementia, alterations of high-order brain functions, and movement disorders. Double-stranded DNA breaks are a lethal form of DNA damage and are typically repaired via non-homologous end joining and homologous recombination. However, in AD brain, repair mechanism is disrupted, leading to a cascade of events, cognitive dysfunction, organ failure and reduced lifespan. Increased circulating cell-free DNA in the blood, cerebrospinal fluid, and urine in patients with AD, can be used as early detectable biomarkers for AD. The purpose of our article is to explore the potential uses of cell-free DNA and double-stranded DNA breaks as prognostic markers for AD and examine the recent research on the application of these markers in studies.

Creating Cultural and Lifestyle Awareness About Dementia and Co-morbidities.

Dementia is a major health concern in society, particularly in the aging population. It is alarmingly increasing in ethnic minorities such as Native Americans, African Americans, Hispanics/Latinos, and to some extent Asians. With increasing comorbidities of dementia such as diabetes, obesity, and hypertension, dementia rates are expected to increase in the next decade and beyond. Understanding and treating dementia, as well as determining how to prevent it, has become a healthcare priority across the globe for all races and genders. Awareness about dementia and its consequences such as healthcare costs, and caregiver burden are immediate needs to be addressed. Therefore, it is high time for all of us to create awareness about dementia in society, particularly among Hispanics/Latinos, Native Americans, and African Americans. In the current article, we discuss the status of dementia, cultural, and racial impacts on dementia diagnosis and care, particularly in Hispanic populations, and possible steps to increase dementia awareness. We also discussed factors that need to be paid attention to, including, cultural & language barriers, low socioeconomic status, limited knowledge/education, religious/spiritual beliefs and not accepting modern medicine/healthcare facilities. Our article also covers both mental & physical health issues of caregivers who are living with patients with dementia, Alzheimer's disease, and Alzheimer's disease-related dementias. Most importantly, we discussed possible measures to create awareness about dementia, including empowering community advocacy, promoting healthy lifestyle choices, education on the impact of nutrition, encouraging community participation, and continued collaboration and evaluation of the success of dementia awareness.

Overlooked Cases of Mild Cognitive Impairment: Implications to Early Alzheimer's Disease.

Mild cognitive impairment (MCI) marks the initial phase of memory decline or other cognitive functions like language or spatial perception, while individuals typically retain the capacity to carry out everyday tasks independently. Our comprehensive article investigates the intricate landscape of cognitive disorders, focusing on MCI and Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD). The study aims to understand the signs of MCI, early Alzheimer's disease, and healthy brain aging while assessing factors influencing disease progression, pathology development and susceptibility. A systematic literature review of over 100 articles was conducted, emphasizing MCI, AD and ADRD within the elderly populations. The synthesis of results reveals significant findings regarding ethnicity, gender, lifestyle, comorbidities, and diagnostic tools. Ethnicity was found to influence MCI prevalence, with disparities observed across diverse populations. Gender differences were evident in cognitive performance and decline, highlighting the need for personalized management strategies. Lifestyle factors and comorbidities were identified as crucial influencers of cognitive health. Regarding diagnostic tools, the Montreal Cognitive Assessment (MoCA) emerged as superior to the Mini-Mental State Examination (MMSE) in early MCI detection. Overall, our article provides insights into the multifaceted nature of cognitive disorders, emphasizing the importance of tailored interventions and comprehensive assessment strategies for effective cognitive health management.

Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems.

The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.

Cell-Free DNA As Peripheral Biomarker of Alzheimer's Disease.

Alzheimer's disease (AD) and Alzheimer's disease-related disorders (ADRD) are progressive neurodegenerative diseases without cure. Alzheimer's disease occurs in 2 forms, early-onset familial AD and late-onset sporadic AD. Early-onset AD is a rare (~1%), autosomal dominant, caused by mutations in presenilin-1, presenilin-2, and amyloid precursor protein genes and the other is a late-onset, prevalent and is evolved due to age-associated complex interactions between environmental and genetic factors, in addition to apolipoprotein E4 polymorphism. Cellular senescence, promoting the impairment of physical and mental functions is constituted to be the main cause of aging, the primary risk factor for AD, which results in progressive loss of cognitive function, memory, and visual-spatial skills for an individual to live or act independently. Despite significant progress in the understanding of the biology and pathophysiology of AD, we continue to lack definitive early detectable biomarkers and/or drug targets that can be used to delay the development of AD and ADRD in elderly populations. However, recent developments in the studies of DNA double-strand breaks result in the release of fragmented DNA into the bloodstream and contribute to higher levels of cell-free DNA (cf-DNA). This fragmented cf-DNA can be released into the bloodstream from various cell types, including normal cells and cells undergoing apoptosis or necrosis and elevated levels of cf-DNA in the blood have the potential to serve as blood blood-based biomarker for early detection of AD and ADRD. The overall goal of our study is to discuss the latest developments in circulating cell-free DNA into the blood in the progression of AD and ADRD. Our article summarized the status of research on double-strand breaks and circulating cell-free DNA in both healthy and disease states and how these recent developments can be used to develop early detectable biomarkers for AD and ADRD. Our article also discussed the impact of lifestyle and epigenetic factors that are involved in DNA double-strand breaks and circulating cell-free DNA in AD and ADRD.

SuperAgers and Centenarians, Dynamics of Healthy Ageing with Cognitive Resilience.

Graceful healthy ageing and extended longevity is the most desired goal for human race. The process of ageing is inevitable and has a profound impact on the gradual deterioration of our physiology and health since it triggers the onset of many chronic conditions like dementia, osteoporosis, diabetes, arthritis, cancer, and cardiovascular disease. However, some people who lived/live more than 100 years called 'Centenarians" and how do they achieve their extended lifespans are not completely understood. Studying these unknown factors of longevity is important not only to establish a longer human lifespan but also to manage and treat people with shortened lifespans suffering from age-related morbidities. Furthermore, older adults who maintain strong cognitive function are referred to as "SuperAgers" and may be resistant to risk factors linked to cognitive decline. Investigating the mechanisms underlying their cognitive resilience may contribute to the development of therapeutic strategies that support the preservation of cognitive function as people age. The key to a long, physically, and cognitively healthy life has been a mystery to scientists for ages. Developments in the medical sciences helps us to a better understanding of human physiological function and greater access to medical care has led us to an increase in life expectancy. Moreover, inheriting favorable genetic traits and adopting a healthy lifestyle play pivotal roles in promoting longer and healthier lives. Engaging in regular physical activity, maintaining a balanced diet, and avoiding harmful habits such as smoking contribute to overall well-being. The synergy between positive lifestyle choices, access to education, socio-economic factors, environmental determinants and genetic supremacy enhances the potential for a longer and healthier life. Our article aims to examine the factors associated with healthy ageing, particularly focusing on cognitive health in centenarians. We will also be discussing different aspects of ageing including genomic instability, metabolic burden, oxidative stress and inflammation, mitochondrial dysfunction, cellular senescence, immunosenescence, and sarcopenia.

Is Effective Recruitment Strategy Critical to Assess Brain Cognitive Function of Super Agers in Rural West Texas.

Our commentary aims to elucidate the importance of participant recruitment strategy in healthy brain aging study, particularly in rural West Texas, where more than 50% of the population are Hispanics and Latinos. The objective of our health aging study is to investigate the possible influence of biological, sociodemographic, and lifestyle factors on the occurrence of chronic diseases and dementia in the aging populations of West Texas. The success of this initiative is, in large part, reliant on high-quality, effective recruitment of participants. To that end, we propose an increase in our strategic recruitment efforts for both healthy, cognitively superior agers as well as those with mild cognitive impairment and patients with Alzheimer's disease in rural west Texas. We discussed, multi-advertising approaches, including ads in the local newspapers, local TV Channels and poster boards in senior centers.

Unveiling the Role of Novel miRNA PC-5P-12969 in Alleviating Alzheimer's Disease.

Background: The intricate and complex molecular mechanisms that underlie the progression of Alzheimer's disease (AD) have prompted a concerted and vigorous research endeavor aimed at uncovering potential avenues for therapeutic intervention. Objective: This study aims to elucidate the role of miRNA PC-5P-12969 in the pathogenesis of AD. Methods: We assessed the differential expression of miRNA PC-5P-12969 in postmortem AD brains, AD animal and cell models using real-time reverse-transcriptase RT-PCR, we also checked the gene and protein expression of GSK3α and APP. Results: Our investigation revealed a notable upregulation of miRNA PC-5P-12969 in postmortem brains of AD patients, in transgenic mouse models of AD, and in mutant APP overexpressing-HT22 cells. Additionally, our findings indicate that overexpression of miRNA PC-5P-12969 exerts a protective effect on cell survival, while concurrently mitigating apoptotic cell death. Further-more, we established a robust and specific interaction between miRNA PC-5P-12969 and GSK3α. Our luciferase reporter assays provided confirmation of the binding between miRNA PC-5P-12969 and the 3'-UTR of the GSK3α gene. Manipulation of miRNA PC-5P-12969 levels in cellular models of AD yielded noteworthy alterations in the gene and protein expression levels of both GSK3α and APP. Remarkably, the manipulation of miRNA PC-5P-12969 levels yielded significant enhancements in mitochondrial respiration and ATP production, concurrently with a reduction in mitochondrial fragmentation, thus unveiling a potential regulatory role of miRNA PC-5P-12969 in these vital cellular processes. Conclusions: In summary, this study sheds light on the crucial role of miRNA PC-5P-12969 and its direct interaction with GSK3α in the context of AD.

Mechanisms of pain in aging and age-related conditions: Focus on caregivers.

Pain is a complex, subjective experience that can significantly impact quality of life, particularly in aging individuals, by adversely affecting physical and emotional well-being. Whereas acute pain usually serves a protective function, chronic pain is a persistent pathological condition that contributes to functional deficits, cognitive decline, and emotional disturbances in the elderly. Despite substantial progress that has been made in characterizing age-related changes in pain, complete mechanistic details of pain processing mechanisms in the aging patient remain unknown. Pain is particularly under-recognized and under-managed in the elderly, especially among patients with Alzheimer's disease (AD), Alzheimer's disease-related dementias (ADRD), and other age-related conditions. Furthermore, difficulties in assessing pain in patients with AD/ADRD and other age-related conditions may contribute to the familial caregiver burden. The purpose of this article is to discuss the mechanisms and risk factors for chronic pain development and persistence, with a particular focus on age-related changes. Our article also highlights the importance of caregivers working with aging chronic pain patients, and emphasizes the urgent need for increased legislative awareness and improved pain management in these populations to substantially alleviate caregiver burden.

A Combinational Therapy for Preventing and Delaying the Onset of Alzheimer's Disease: A Focus on Probiotic and Vitamin Co-Supplementation.

Alzheimer's disease is a progressive neurodegenerative disorder with a complex etiology, and effective interventions to prevent or delay its onset remain a global health challenge. In recent years, there has been growing interest in the potential role of probiotic and vitamin supplementation as complementary strategies for Alzheimer's disease prevention. This review paper explores the current scientific literature on the use of probiotics and vitamins, particularly vitamin A, D, E, K, and B-complex vitamins, in the context of Alzheimer's disease prevention and management. We delve into the mechanisms through which probiotics may modulate gut-brain interactions and neuroinflammation while vitamins play crucial roles in neuronal health and cognitive function. The paper also examines the collective impact of this combinational therapy on reducing the risk factors associated with Alzheimer's disease, such as oxidative stress, inflammation, and gut dysbiosis. By providing a comprehensive overview of the existing evidence and potential mechanisms, this review aims to shed light on the promise of probiotic and vitamin co-supplementation as a multifaceted approach to combat Alzheimer's disease, offering insights into possible avenues for future research and clinical application.

Correction: Reddy et al. Rlip Reduction Induces Oxidative Stress and Mitochondrial Dysfunction in Mutant Tau-Expressed Immortalized Hippocampal Neurons: Mechanistic Insights. Cells 2023, 12, 1646.

The authors wish to make the following changes to their paper [...].

DDQ anti-aging properties expressed with improved mitophagy in mutant tau HT22 neuronal cells.

The purpose of our study is to develop age-related phosphorylated tau (p-tau) inhibitors, for Alzheimer's disease (AD). There are wide-ranging therapeutic molecules available in the market and tested for age-related p-tau inhibition to enhance phosphatase activity and microtubule stability in AD neurons. Until now there are no such small molecules claimed to show promising results to delay the disease process of AD. However, a recently developed molecule, DDQ, has been shown to reduce abnormal protein-protein interactions and protect neurons from mutant protein-induced toxicities in the disease process. In addition, DDQ reduced age- and Aß-induced oxidative stress, mitochondrial dysfunction, and synaptic toxicity. To date, there are no published reports on the p-tau interaction of DDQ and Sirt3 upregulation with CREB-mediated mitophagy activation in AD neurons. In the current study, HT22 cells were transfected with mutant Tau (mTau) cDNA and treated with the novel molecule DDQ. Cell survival, immunoblotting, and immunofluorescence analysis were conducted to assess cell viability and synaptic and mitophagy proteins in treated and untreated cell groups. As expected, we found cell survival was decreased in mTau-HT22 cells when compared with control HT22 cells. However, cell survival was increased in DDQ-treated mTau-HT22 cells when compared with mTau HT22 cells. P-tau and total tau proteins were significantly reduced in DDQ-treated mTau-HT22 cells, and MAP2 levels were increased. Anti-aging proteins like Sirt3, and CREB levels were increased in DDQ-treated HT22 cells and also in mTau-HT22 cells treated DDQ. Mitophagy proteins were decreased in mTau-HT22 cells and these were increased in DDQ-treated mTau-HT22 cells. These observations strongly suggest that DDQ has anti-p-tau and anti-aging properties, via Sirt3 overexpression and increased mitophagy proteins. Our study findings may have implications for healthy aging to the development of p-tau targeted therapeutics in AD and tauopathies.

Targeting long non-coding RNAs in cancer therapy using CRISPR-Cas9 technology: A novel paradigm for precision oncology.

Cancer is the second leading cause of death worldwide, despite recent advances in its identification and management. To improve cancer patient diagnosis and care, it is necessary to identify new biomarkers and molecular targets. In recent years, long non-coding RNAs (lncRNAs) have surfaced as important contributors to various cellular activities, with growing proof indicating their substantial role in the genesis, development, and spread of cancer. Their unique expression profiles within specific tissues and their wide-ranging functionalities make lncRNAs excellent candidates for potential therapeutic intervention in cancer management. They are implicated in multiple hallmarks of cancer, such as uncontrolled proliferation, angiogenesis, and immune evasion. This review article explores the innovative application of CRISPR-Cas9 technology in targeting lncRNAs as a cancer therapeutic strategy. The CRISPR-Cas9 system has been widely applied in functional genomics, gene therapy, and cancer research, offering a versatile platform for lncRNA targeting. CRISPR-Cas9-mediated targeting of lncRNAs can be achieved through CRISPR interference, activation or the complete knockout of lncRNA loci. Combining CRISPR-Cas9 technology with high-throughput functional genomics makes it possible to identify lncRNAs critical for the survival of specific cancer subtypes, opening the door for tailored treatments and personalised cancer therapies. CRISPR-Cas9-mediated lncRNA targeting with other cutting-edge cancer therapies, such as immunotherapy and targeted molecular therapeutics can be used to overcome the drug resistance in cancer. The synergy of lncRNA research and CRISPR-Cas9 technology presents immense potential for individualized cancer treatment, offering renewed hope in the battle against this disease.

Protective effects of SSRI, Citalopram in mutant APP and mutant Tau expressed dorsal raphe neurons in Alzheimer's disease.

Depression is among the most common neuropsychiatric comorbidities in Alzheimer's disease (AD) and other Tauopathies. Apart from its anti-depressive and anxiolytic effects, selective serotonin reuptake inhibitor (SSRI) treatment also offers intracellular modifications that may help to improve neurogenesis, reduce amyloid burden & Tau pathologies, and neuroinflammation in AD. Despite its multifaceted impact in the brain, the exact physiological and molecular mechanism by which SSRIs such as Citalopram improve neurogenesis and synaptogenesis in dementia is poorly understood. In the current study, we investigated the protective role of SSRI, Citalopram, in serotonergic, medullary raphe neurons (RN46A-B14). RN46A-B14 cells were transfected with wild-type and mutant APP and Tau cDNAs for 24 h and then treated with 20 µM Cit for 24 h. We then assessed mRNA and protein levels of pTau, total Tau, serotonin related proteins such as TPH2, SERT, and 5HTR1a, synaptic proteins and the cytoskeletal structure. We also assessed cell survival, mitochondrial respiration and mitochondrial morphology. The mutant APP and Tau transfected cells showed increased levels of serotonin related proteins and mRNA, while the mRNA and protein levels of synaptic proteins were downregulated. Citalopram treatment significantly reduced pathologically pTau level along with the serotonin related protein levels. On the other hand, there was a significant increase in the mRNA and protein levels of synaptic genes and cytoskeletal structure in the treated groups. Further, Citalopram also improved cell survival, mitochondrial respiration and mitochondrial morphology in the treated cells that express mAPP and mTau. Taken together these findings suggest Citalopram could not only be a promising therapeutic drug for treating patients with depression, but also for AD patients.

The role of RLIP76 in oxidative stress and mitochondrial dysfunction: Evidence based on autopsy brains from Alzheimer's disease patients.

Several converging lines of evidence from our group support a potential role of RLIP76 (AKA Rlip) in neurodegenerative disorders, including Alzheimer's Disease (AD). However, the role of Rlip in Alzheimer's and other neurodegenerative diseases is not well understood. The purpose of the present study is to determine the role of Rlip in the brains of AD patients and control subjects. To achieve our goals, we used frozen tissues and formalin-fixed paraffin-embedded postmortem brains from AD patients of different Braak stages and age-matched control subjects. Our immunohistology and immunoblotting blotting analysis revealed that expression of Rlip protein gradually and significantly decreased (p = 0.0001) with AD progression, being lowest in Braak stage IV-V. Rlip was colocalized with Amyloid beta (Aß) and phosphorylated tau (p-Tau) as observed by IHC staining and co-immunoprecipitation studies. Lipid peroxidation (4-HNE generation) and H2O2 production were significantly higher (p = 0.004 and 0.0001 respectively) in AD patients compared to controls, and this was accompanied by lower ATP production in AD (p = 0.0009). Oxidative DNA damage was measured by 8-Hydroxyguanosine (8-OHdG) in tissue lysates by ELISA and COMET assay. AD 8-OHdG levels were significantly higher (p = 0.0001) compared to controls. COMET assay was performed in brain cells, isolated from frozen postmortem samples. The control samples showed minimal DNA in comets representing few DNA strand breaks (<20 %), (score-0-1). However, the AD group showed an average of 50 % to 65 % of DNA in comet tails (score-4-5) indicating numerous DNA strand breaks. The difference between the two groups was significant (p = 0.001), as analyzed by Open Comet by ImageJ. Elevated DNA damage was further examined by western blot analysis for phosphorylated histone variant H2AX (γH2AX). Induction of γH2AX was very significant (p < 0.0001) and confirmed the presence of double-strand breaks in DNA. Overall, our results indicate an important role for Rlip in maintaining neuronal health and homeostasis by suppressing cellular oxidative stress and DNA damage. Based on our findings, we cautiously conclude that Rlip is a promising therapeutic target for Alzheimer's disease.

Alzheimer's disease and Alzheimer's disease-related dementias in Hispanics: Identifying influential factors and supporting caregivers.

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are the primary public health concerns in the United States and around the globe. AD/ADRD are irreversible mental illnesses that primarily impair memory and thought processes and may lead to cognitive decline among older individuals. The prevalence of AD/ADRD is higher in Native Americans, followed by African Americans and Hispanics. Increasing evidence suggests that Hispanics are the fastest-growing ethnic population in the USA and worldwide. Hispanics develop clinical symptoms of AD/ADRD and other comorbidities nearly seven years earlier than non-Hispanic whites. The consequences of AD/ADRD can be challenging for patients, their families, and caregivers. There is a significant increase in the burden of illness, primarily affecting Hispanic/Latino families. This is partly due to their strong sense of duty towards family, and it is exacerbated by the inadequacy of healthcare and community services that are culturally and linguistically suitable and responsive to their needs. With an increasing age population, low socioeconomic status, low education, high genetic predisposition to age-related conditions, unique cultural habits, and social behaviors, Hispanic Americans face a higher risk of AD/ADRD than other racial/ethnic groups. Our article highlights the status of Hispanic older adults with AD/ADRD. We also discussed the intervention to improve the quality of life in Hispanic caregivers.

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 17ß-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.