Selective estrogen receptor modulators (SERMs) affect cholesterol homeostasis through the master regulators SREBP and LXR

Fernández-Suárez, María E.; Daimiel, Lidia; Villa-Turégano, Gemma; Pavón, María Vázquez; Busto, Rebeca; Escolà‐Gil, Joan Carles; Platt, Frances M.; Lasunción, Miguel A.; Martı́nez-Botas, Javier; Gómez-Coronado, Diego

doi:10.1016/j.biopha.2021.111871

Cited by 21 publications

(10 citation statements)

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“…It is unequivocal that oncogenic signaling in the breast is influenced by a plethora of processes, including cholesterol and its diverse metabolites, and SERMs modulate a number of these factors/signaling for combating BCs. Regardless of the mechanism involved, there is increasing evidence that SERMs and/or tamoxifen, by inhibiting 5,6-EC metabolites, enzymes in the cholesterol biosynthetic pathway, and LXR regulatory events, prevent hormone-sensitive BCs [ 65 , 66 , 67 , 68 ]. Based on the above considerations, it is conceivable that SERMs affect StAR, or other relevant cholesterol transporters, such as STARD3, in ER+/PR+ BCs, and require future investigations.…”

Section: Estrogen and Its Receptors 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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Section: Estrogen and Its Receptors 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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“…For example, steroid biosynthesis pathway (METABOLISM OF STEROIDS) was enriched with upregulated genes after treated with selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene in HA1E cells (FDR< 0.0001, Figures 5B,C ). SERMs are a group of non-steroidal drugs with the ability to bind to estrogen receptors and can upregulate steroid metabolism-related genes by interacting with sterol regulatory element-binding protein (SREBP-2) ( Fernández-Suárez et al, 2021 ). Moreover, important enzymes involved in the “METABOLISM OF STEROIDS” pathway such as farnesyl diphosphate synthetase (FDPS), 7-dehydrocholesterol reductase (DHCR7), methylsterol monooxygenase1 (MSMO1) were upregulated by tamoxifen treatment in a dose-dependent manner ( Figure 5F ).…”

Section: Resultsmentioning

confidence: 99%

A Computational Framework to Characterize the Cancer Drug Induced Effect on Aging Using Transcriptomic Data

et al. 2022

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Cancer treatments such as chemotherapies may change or accelerate aging trajectories in cancer patients. Emerging evidence has shown that “omics” data can be used to study molecular changes of the aging process. Here, we integrated the drug-induced and normal aging transcriptomic data to computationally characterize the potential cancer drug-induced aging process in patients. Our analyses demonstrated that the aging-associated gene expression in the GTEx dataset can recapitulate the well-established aging hallmarks. We next characterized the drug-induced transcriptomic changes of 28 FDA approved cancer drugs in brain, kidney, muscle, and adipose tissues. Further drug-aging interaction analysis identified 34 potential drug regulated aging events. Those events include aging accelerating effects of vandetanib (Caprelsa®) and dasatinib (Sprycel®) in brain and muscle, respectively. Our result also demonstrated aging protective effect of vorinostat (Zolinza®), everolimus (Afinitor®), and bosutinib (Bosulif®) in brain.

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“…Some studies had confirmed that estrogen plays a positive role in maintaining a low level of TC. And the loss of the protective effect of estrogen will significantly increase the obesity rate and the risk of dyslipidemia in middle-aged and elderly women [12][13][14]. This indicated that more attention should be paid to the lipids level in this group people.…”

Section: Discussionmentioning

confidence: 99%

Associations of environmental factors with total cholesterol level of middle-aged and elderly people in China

Pei

et al. 2022

BMC Public Health

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Background Dyslipidemia is a key factor causing cardio cerebrovascular diseases, and the total cholesterol (TC) is an important lipid indicator among them. Studies have shown that environmental factors have a strong association with TC levels. Previous studies only focused on the seasonal variation of TC level and the short-term effects of some environmental factors on TC level over time, and few studies explored the geographical distribution of TC level and quantified the impact of environmental factors in space. Methods Based on blood test data which was from China Health and Retirement Longitudinal Study (Charls) database, this study selected the TC level test data of middle-aged and elderly people in China in 2011 and 2015, and collected data from 665 meteorological stations and 1496 air pollutant monitoring stations in China. After pretreatment, the spatial distribution map of TC level was prepared and the regional statistics were made. GeoDetector and geographically weighted regression (GWR) were used to measure the relationship between environmental factors and TC level. Results The TC level of middle-aged and elderly in China was higher in females than in males, and higher in urban areas than in rural areas, showing a clustered distribution. The high values were mainly in South China, Southwest China and North China. Temperature, humidity, PM10 and PM2.5 were significant environmental factors affecting TC level of middle-aged and elderly people. The impact of pollutants was more severe in northern China, and TC level in southern China was mainly affected by meteorological factors. Conclusions There were gender and urban-rural differences in TC levels among the middle-aged and elderly population in China, showing aggregation in geographical distribution. Meteorological factors and air pollutants may be very important control factors, and their influencing mechanism needs further study.

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Selective estrogen receptor modulators (SERMs) affect cholesterol homeostasis through the master regulators SREBP and LXR

Cited by 21 publications

References 58 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

A Computational Framework to Characterize the Cancer Drug Induced Effect on Aging Using Transcriptomic Data

Associations of environmental factors with total cholesterol level of middle-aged and elderly people in China

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