Role of cholesterol metabolism in the anticancer pharmacology of selective estrogen receptor modulators

Gómez-Coronado, Diego; Lasunción, Miguel A.; Martı́nez-Botas, Javier; Fernández-Suárez, María E.

doi:10.1016/j.semcancer.2020.08.015

Cited by 16 publications

(6 citation statements)

References 323 publications

(496 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, a great deal of clinical research has focused on the roles of ER in promoting breast cancer or osteoporosis, and several FDA-approved drugs exist to this day such as tamoxifen, toremifene, raloxifene, and fulvestrant that target SERMs or selective downregulation of ER in mammillary cells [ 143 , 144 ]. The downside of these drugs is that they may produce breast cancer resistance effects, and therefore more work remains to increase their efficacy [ 145 ]. To summarize, although many neuroscience benchwork studies have uncovered the fine molecular actions of ER in the brain to increase energy expenditure and decrease food intake (e.g., [ 146 ]), it is curious that no FDA-approved SERM exists for treating metabolic disorders caused by dietary stress or physical stress.…”

Section: Discussionmentioning

confidence: 99%

Estrogenic Action in Stress-Induced Neuroendocrine Regulation of Energy Homeostasis

Krolick

Shi

2022

Cells

View full text Add to dashboard Cite

Estrogens are among important contributing factors to many sex differences in neuroendocrine regulation of energy homeostasis induced by stress. Research in this field is warranted since chronic stress-related psychiatric and metabolic disturbances continue to be top health concerns, and sex differences are witnessed in these aspects. For example, chronic stress disrupts energy homeostasis, leading to negative consequences in the regulation of emotion and metabolism. Females are known to be more vulnerable to the psychological consequences of stress, such as depression and anxiety, whereas males are more vulnerable to the metabolic consequences of stress. Sex differences that exist in the susceptibility to various stress-induced disorders have led researchers to hypothesize that gonadal hormones are regulatory factors that should be considered in stress studies. Further, estrogens are heavily recognized for their protective effects on metabolic dysregulation, such as anti-obesogenic and glucose-sensing effects. Perturbations to energy homeostasis using laboratory rodents, such as physiological stress or over-/under- feeding dietary regimen prevalent in today’s society, offer hints to the underlying mechanisms of estrogenic actions. Metabolic effects of estrogens primarily work through estrogen receptor α (ERα), which is differentially expressed between the sexes in hypothalamic nuclei regulating energy metabolism and in extrahypothalamic limbic regions that are not typically associated with energy homeostasis. In this review, we discuss estrogenic actions implicated in stress-induced sex-distinct metabolic disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Estrogenic Action in Stress-Induced Neuroendocrine Regulation of Energy Homeostasis

Krolick

Shi

2022

Cells

View full text Add to dashboard Cite

show abstract

“…Selective oestrogen receptor modulators (SERMs) act as oestrogen agonists or antagonists in a tissue-selective manner, depending on the target tissue [ 31 ]. Tamoxifen, toremifene, and raloxifene are the first three SERMs approved for clinical use [ 32 ]. Tamoxifen is the most commonly used SERM and acts as an oestrogen receptor antagonist in breast tissue but as a partial agonist in other tissues such as the endometrium and bone [ 32 ].…”

Section: The Mainstream Methods Of Managing Menopausementioning

confidence: 99%

“…Tamoxifen, toremifene, and raloxifene are the first three SERMs approved for clinical use [ 32 ]. Tamoxifen is the most commonly used SERM and acts as an oestrogen receptor antagonist in breast tissue but as a partial agonist in other tissues such as the endometrium and bone [ 32 ]. Although tamoxifen may treat osteoporosis and reduce the incidence of cardiovascular disease and treat breast cancer, its long-term usage unfortunately has side effects such as hot flashes and uterine cancer [ 33 ].…”

Section: The Mainstream Methods Of Managing Menopausementioning

confidence: 99%

Lactic Acid Bacteria: A Promising Tool for Menopausal Health Management in Women

Chen

Wang

et al. 2022

Nutrients

View full text Add to dashboard Cite

Menopause is a period during which women undergo dramatic hormonal changes. These changes lead to physical and mental discomfort, are greatly afflictive, and critically affect women’s lives. However, the current safe and effective management measures for women undergoing menopause are insufficient. Several probiotic functions of lactic acid bacteria (LAB) have been recognized, including alleviation of lactose intolerance, protection of digestive tract health, activation of the immune system, protection against infections, improvement of nutrient uptake, and improvement of the microbiota. In this review, we highlight the currently available knowledge of the potential protective effects of LAB on preventing or mitigating menopausal symptoms, particularly in terms of maintaining balance in the vaginal microbiota, reducing bone loss, and regulating the nervous system and lipid metabolism. Given the increasing number of women entering menopause and the emphasis on the management of menopausal symptoms, LAB are likely to soon become an indispensable part of clinical/daily care for menopausal women. Herein, we do not intend to provide a comprehensive analysis of each menopausal disorder or to specifically judge the reliability and safety of complementary therapies; rather, we aim to highlight the potential roles of LAB in individualized treatment strategies for the clinical management of menopause.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Role of cholesterol metabolism in the anticancer pharmacology of selective estrogen receptor modulators

Cited by 16 publications

References 323 publications

Estrogenic Action in Stress-Induced Neuroendocrine Regulation of Energy Homeostasis

Estrogenic Action in Stress-Induced Neuroendocrine Regulation of Energy Homeostasis

Lactic Acid Bacteria: A Promising Tool for Menopausal Health Management in Women

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

Contact Info

Product

Resources

About