Regulation of aromatase in cancer

Molehin, Deborah; Rasha, Fahmida; Rahman, Rakhshanda Layeequr; Pruitt, Kevin

doi:10.1007/s11010-021-04099-0

Cited by 20 publications

(14 citation statements)

References 185 publications

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“…In support of these findings, studies have demonstrated that cholesterol and its metabolites, especially 27-hydroxycholesterol, play crucial roles in the pathophysiology of luminal BC subtypes [32][33][34][35]. Nevertheless, dysregulation of the steroidogenic machinery, involving androgen and E2 biosynthesis, has been linked to BC pathogenesis [10,36,37]. Our present data extend these observations by elucidating the molecular events by which StAR drives hormone-dependent breast tumorigenesis.…”

Section: Discussionsupporting

confidence: 82%

“…The occurrence of genetic abnormality, involving gene amplifications and/or oncogene activation, is a fundamental event in cancer progression and survival. There is increasing evidence that intra-tumoral E2 buildup in malignant breast tissue is due to en-hanced expression and activity of aromatase [11,17,31,37,38]. In keeping with this, AIs have been the mainstay treatment for BCs, and other estrogen dependent cancers/disorders, in post-menopausal women.…”

Section: Discussionmentioning

confidence: 96%

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Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer

Manna

Ramachandran

Pradeepkiran

et al. 2023

IJMS

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Breast cancer (BC) is primarily triggered by estrogens, especially 17β-estradiol (E2), which are synthesized by the aromatase enzyme. While all steroid hormones are derived from cholesterol, the rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. Herein, we demonstrate that StAR mRNA expression was aberrantly high in human hormone-dependent BC (MCF7, MDA-MB-361, and T-47D), modest in hormone-independent triple negative BC (TNBC; MDA-MB-468, BT-549, and MDA-MB-231), and had little to none in non-cancerous mammary epithelial (HMEC, MCF10A, and MCF12F) cells. In contrast, these cell lines showed abundant expression of aromatase (CYP19A1) mRNA. Immunofluorescence displayed qualitatively similar patterns of both StAR and aromatase expression in various breast cells. Additionally, three different transgenic (Tg) mouse models of spontaneous breast tumors, i.e., MMTV-Neu, MMTV-HRAS, and MMTV-PyMT, demonstrated markedly higher expression of StAR mRNA/protein in breast tumors than in normal mammary tissue. While breast tumors in these mouse models exhibited higher expression of ERα, ERβ, and PR mRNAs, their levels were undetected in TNBC tumors. Accumulation of E2 in plasma and breast tissues, from MMTV-PyMT and non-cancerous Tg mice, correlated with StAR, but not with aromatase, signifying the importance of StAR in governing E2 biosynthesis in mammary tissue. Treatment with a variety of histone deacetylase inhibitors (HDACIs) in primary cultures of enriched breast tumor epithelial cells, from MMTV-PyMT mice, resulted in suppression of StAR and E2 levels. Importantly, inhibition of StAR, concomitant with E2 synthesis, by various HDACIs, at clinical and preclinical doses, in MCF7 cells, indicated therapeutic relevance of StAR in hormone-dependent BCs. These findings provide insights into the molecular events underlying the differential expression of StAR in human and mouse cancerous and non-cancerous breast cells/tissues, highlighting StAR could serve not only as a novel diagnostic maker but also as a therapeutic target for the most prevalent hormone-sensitive BCs.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 96%

Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer

Manna

Ramachandran

Pradeepkiran

et al. 2023

IJMS

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“…Malfunction in the steroidogenic pathway, involving androgen and/or estrogen biosynthesis, has been implicated in the pathogenesis of a number of cancers, including the most prevalent hormone-sensitive BCs [ 2 , 24 , 77 ]. We reported that ER+/PR+ BCs exert a markedly higher expression of StAR, along with increased E2, and their levels are little to none in either normal mammary epithelial cells or TNBCs [ 23 ].…”

Section: Functional Relevance Of Star and Steroidogenic Machinery In Bcsmentioning

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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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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“…Aromatase inhibitors (AIs) interfere with the body's ability to generate estrogen from androgens by inhibiting the action of the aromatase enzyme [4]. Due to their effectiveness 2 of 11 in hormone receptor (HR)-positive breast cancers, AIs represent a backbone therapy, particularly in postmenopausal women [5]. However, AIs administration has been related to common side effects that represent a critical issue in the current literature [6,7].…”

Section: Introductionmentioning

confidence: 99%

Physical Exercise with or without Whole-Body Vibration in Breast Cancer Patients Suffering from Aromatase Inhibitor—Induced Musculoskeletal Symptoms: A Pilot Randomized Clinical Study

Sire

Lippi

Ammendolia

et al. 2021

JPM

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In this study, we aimed to assess the safety and efficacy of physical exercise, with or without whole-body vibration (WBV), in patients with aromatase inhibitor-induced musculoskeletal symptoms (AIMSS). Eligible patients were adults (≥18 years) with a history of breast cancer and current AIMSS. Enrolled patients (n = 22) were randomly assigned 1:1 to receive physical exercise combined with WBV or sham WBV for 4 weeks. The primary endpoint was pain intensity measured by numerical pain rating scale (NPRS). The secondary endpoints were muscle strength, physical function, physical performance, and quality of life. The WBV group (mean age: 51.73 ± 10.73 years; body mass index (BMI): 25.56 ± 5.17 kg/m2) showed a statistically significant pain reduction (NPRS: 6.82 ± 1.17 vs. 5.73 ± 1.01; p = 0.031), whereas patients in the sham WBV group (mean age: 58.55 ± 9.71 years; BMI: 27.31 ± 3.84 kg/m2), did not reach statistical significance (NPRS: 6.91 ± 2.02 vs. 5.91 ± 2.51; p = 0.07). Concurrently, muscle strength, physical performance, and quality of life significantly improved in both groups, without significant differences between groups. No dropouts and no side effects were recorded. Both patients and the physical therapist reported a high level of satisfaction with the intervention. Our findings suggest that physical exercise and WBV combination might be a safe therapeutic option for improving the rehabilitative management of patients with AIMSS.

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Regulation of aromatase in cancer

Cited by 20 publications

References 185 publications

Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer

Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer

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

Physical Exercise with or without Whole-Body Vibration in Breast Cancer Patients Suffering from Aromatase Inhibitor—Induced Musculoskeletal Symptoms: A Pilot Randomized Clinical Study

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