Genomic Profiling of the Steroidogenic Acute Regulatory Protein in Breast Cancer: In Silico Assessments and a Mechanistic Perspective

Manna, Pulak R.; Ahmed, Ahsen U; Yang, Shengping; Narasimhan, Madhusudhanan; Cohen‐Tannoudji, Joëlle; Slominski, Andrzej; Pruitt, Kevin

doi:10.3390/cancers11050623

Cited by 15 publications

(26 citation statements)

References 71 publications

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“…BCs are frequently classified based on immunohistochemical (IHC) markers for ER (specifically ERα, but not ERβ), PR, and HER2 into the following subtypes: luminal A, luminal B, HER2, normal-like, and TNBC (in which 15–20% are basal-like) ( Figure 1 ). While luminal A tumors are ER positive (ER+) and/or PR+, and do not express HER2 (HER2−), luminal B subtypes essentially express ER+/PR+ and HER+ [ 2 , 24 , 30 ]. Notably, luminal categories are hormone sensitive and account for over three quarters of all BCs.…”

Section: Overview Of Bc Subtypesmentioning

confidence: 99%

“…While StAR plays an indispensable role in the regulation of steroid biosynthesis, its involvement in BCs remains poorly understood. Conspicuously, we reported that StAR is overexpressed in hormone-responsive BC cells (in comparison with little to none in non-cancerous mammary epithelial cells), in which amplification of the StAR gene is correlated with poor survival of patients afflicted with this deadly disease [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Hormonal and Genetic Regulatory Events in Breast Cancer and Its Therapeutics: Importance of the Steroidogenic Acute Regulatory Protein

et al. 2022

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Estrogen promotes the development and survival of the majority of breast cancers (BCs). Aromatase is the rate-limiting enzyme in estrogen biosynthesis, and it is immensely expressed in both cancerous and non-cancerous breast tissues. Endocrine therapy based on estrogen blockade, by aromatase inhibitors, has been the mainstay of BC treatment in post-menopausal women; however, resistance to hormone therapy is the leading cause of cancer death. An improved understanding of the molecular underpinnings is the key to develop therapeutic strategies for countering the most prevalent hormone receptor positive BCs. Of note, cholesterol is the precursor of all steroid hormones that are synthesized in a variety of tissues and play crucial roles in diverse processes, ranging from organogenesis to homeostasis to carcinogenesis. The rate-limiting step in steroid biosynthesis is the transport of cholesterol from the outer to the inner mitochondrial membrane, a process that is primarily mediated by the steroidogenic acute regulatory (StAR) protein. Advances in genomic and proteomic technologies have revealed a dynamic link between histone deacetylases (HDACs) and StAR, aromatase, and estrogen regulation. We were the first to report that StAR is abundantly expressed, along with large amounts of 17β-estradiol (E2), in hormone-dependent, but not hormone-independent, BCs, in which StAR was also identified as a novel acetylated protein. Our in-silico analyses of The Cancer Genome Atlas (TCGA) datasets, for StAR and steroidogenic enzyme genes, revealed an inverse correlation between the amplification of the StAR gene and the poor survival of BC patients. Additionally, we reported that a number of HDAC inhibitors, by altering StAR acetylation patterns, repress E2 synthesis in hormone-sensitive BC cells. This review highlights the current understanding of molecular pathogenesis of BCs, especially for luminal subtypes, and their therapeutics, underlining that StAR could serve not only as a prognostic marker, but also as a therapeutic candidate, in the prevention and treatment of this life-threatening disease.

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Section: Overview Of Bc Subtypesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hormonal and Genetic Regulatory Events in Breast Cancer and Its Therapeutics: Importance of the Steroidogenic Acute Regulatory Protein

et al. 2022

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“…Steroid hormones are largely synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta, and brain; however, they are also produced in a number of extra-adrenal and -gonadal tissues. Glucocorticoids play critical roles in a wide variety of physiological processes, including regulation of various developmental and homeostatic pathways and display several immune functions 3 , 8 . Their release and production are regulated primarily by ACTH (adrenocorticotropic hormone) and indirectly by CRH (corticotropin releasing hormone) 1 .…”

Section: Introduction: Glucocorticoids Autoimmune and Inflammatory mentioning

confidence: 99%

Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders

et al. 2020

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Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins. Here its side chain is cleaved by CYP11A1 producing pregnenolone. Pregnenolone is converted to cortisol by the enzymes 3-βHSD, CYP17A1, CYP21A2 and CYP11B1. Glucocorticoids play a critical role in the regulation of the immune system and exert their action through the glucocorticoid receptor (GR). Although corticosteroids are primarily produced in the adrenal gland, they can also be produced in a number of extra-adrenal tissue including the immune system, skin, brain, and intestine. Glucocorticoid production is regulated by ACTH, CRH, and cytokines such as IL-1, IL-6 and TNFα. The bioavailability of cortisol is also dependent on its interconversion to cortisone which is inactive, by 11βHSD1/2. Local and systemic glucocorticoid biosynthesis can be stimulated by ultraviolet B, explaining its immunosuppressive activity. In this review, we want to emphasize that dysregulation of extra-adrenal glucocorticoid production can play a key role in a variety of autoimmune diseases including multiple sclerosis (MS), lupus erythematosus (LE), rheumatoid arthritis (RA), and skin inflammatory disorders such as psoriasis and atopic dermatitis (AD). Further research on local glucocorticoid production and its bioavailability may open doors into new therapies for autoimmune diseases.

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“…Cancer is a multifactorial condition with aberrant growth of cells. Alterations in gene expression result in uncontrolled growth of cells involving tumor progression [ 121 , 122 ]. Human genome is mostly transcribed but not translated, and gene amplification, involving oncogene activation, is a key event in the growth and development of cancers.…”

Section: Aging Underlying Medical Conditions and Their Correlation To...mentioning

confidence: 99%

Healthy Immunity on Preventive Medicine for Combating COVID-19

2022

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Immunomodulation is influenced by the consumption of nutrients, and healthy immunity is pivotal to defending an individual from a variety of pathogens. The immune system is a network of intricately regulated biological processes that is comprised of many organs, cellular structures, and signaling molecules. A balanced diet, rich in vitamins, minerals, and antioxidants, is key to a strengthened immune system and, thus, crucial to proper functioning of various physiological activities. Conversely, deficiencies of these micronutrients, involving impaired immunity, are linked to numerous health complications, along with a host of pathologies. Coronavirus disease 2019 (COVID-19) is a dangerous infectious disease caused by a β-form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its genomic variants, which enter host cells upon binding to the angiotensin converting enzyme 2 receptors, and is associated with substantial morbidities and mortalities globally. Patients afflicted with COVID-19 display asymptomatic to severe symptoms, occurrences of which are multifactorial and include diverse immune responses, sex and gender differences, aging, and underlying medical conditions. Geriatric populations, especially men in comparison to women, regardless of their states, are most vulnerable to severe COVID-19-associated infections and complications, with fatal outcomes. Advances in genomic and proteomic technologies help one understand molecular events, including host–pathogen interactions and pathogenesis of COVID-19 and, subsequently, have developed a variety of preventive measures urgently, ranging from mask wearing to vaccination to medication. Despite these approaches, no unique strategy is available today that can effectively prevent and/or treat this hostile disease. As a consequence, the maintenance of a boosted immune system could be considered a high priority of preventive medicine for combating COVID-19. Herein, we discuss the current level of understanding underlining the contribution of healthy immunity and its relevance to COVID-19 molecular pathogenesis, and potential therapeutic strategies, in the management of this devastating disease.

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Genomic Profiling of the Steroidogenic Acute Regulatory Protein in Breast Cancer: In Silico Assessments and a Mechanistic Perspective

Cited by 15 publications

References 71 publications

Hormonal and Genetic Regulatory Events in Breast Cancer and Its Therapeutics: Importance of the Steroidogenic Acute Regulatory Protein

Hormonal and Genetic Regulatory Events in Breast Cancer and Its Therapeutics: Importance of the Steroidogenic Acute Regulatory Protein

Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders

Healthy Immunity on Preventive Medicine for Combating COVID-19

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