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JAMA Jul 2020
Review
Topics: Anticarcinogenic Agents; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Primary Prevention; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Uterine Neoplasms; Venous Thromboembolism
PubMed: 32692377
DOI: 10.1001/jama.2020.9246 -
PloS One 2023Breast cancer is a leading cause of cancer-related morbidity and mortality worldwide, with the highest incidence among women. Among the various subtypes of breast...
Breast cancer is a leading cause of cancer-related morbidity and mortality worldwide, with the highest incidence among women. Among the various subtypes of breast cancer, estrogen-receptor positive (ER+) is the most diagnosed. Estrogen upregulates cyclin D1, which in turn promotes the activity of CDK4/6 and facilitates cell cycle progression. To address this, the first-line treatment for ER+ breast cancer focuses on inhibiting estrogen production by targeting aromatase, the enzyme responsible for the rate-limiting step in estrogen synthesis. Thus, combining CDK4/6 inhibitors with aromatase inhibitors has emerged as a crucial treatment strategy for this type of breast cancer. This approach effectively suppresses estrogen biosynthesis and controls uncontrolled cell proliferation, significantly improving overall survival rates and delayed disease progression. This study aimed to identify compounds that are likely to inhibit CDK4/6 and aromatase simultaneously by using a structure-based drug design strategy. 12,432 approved and investigational drugs were prepared and docked into the active site of CDK6 using HTVS and XP docking modes of Glide resulting in 277 compounds with docking scores ≤ -7 kcal/mol. These compounds were docked into aromatase enzyme using XP mode to give seven drugs with docking scores≤ -6.001 kcal/mol. Furthermore, the shortlisted drugs were docked against CDK4 showing docking scores ranging from -3.254 to -8.254 kcal/mol. Moreover, MM-GBSA for the top seven drugs was calculated. Four drugs, namely ellagic acid, carazolol, dantron, and apomorphine, demonstrated good binding affinity to all three protein targets CDK4/6 and aromatase. Specifically, they exhibited favourable binding free energy with CDK6, with values of -51.92, -53.90, -50.22, and -60.97 kcal/mol, respectively. Among these drugs, apomorphine displayed the most favourable binding free energy with all three protein targets. To further evaluate the stability of the interaction, apomorphine was subjected to a 100 ns molecular dynamics simulation with CDK6. The results indicated the formation of a stable ligand-protein complex. While the results obtained from the MM-GBSA calculation of the binding free energies of the MD conformations of apomorphine showed less favourable binding free energy compared to that obtained post-docking. All these computational findings will provide better structural insight for the development of CDK4/6 and aromatase multi-target inhibitors.
Topics: Female; Humans; Molecular Docking Simulation; Aromatase; Molecular Dynamics Simulation; Apomorphine; Drug Repositioning; Breast Neoplasms; Estrogens; Aromatase Inhibitors; Cyclin-Dependent Kinase 4
PubMed: 37682937
DOI: 10.1371/journal.pone.0291256 -
Diabetes Nov 2020Testosterone (T) affects β-cell function in men and women. T is a prohormone that undergoes intracrine conversion in target tissues to the potent androgen...
Testosterone (T) affects β-cell function in men and women. T is a prohormone that undergoes intracrine conversion in target tissues to the potent androgen dihydrotestosterone (DHT) via the enzyme 5α-reductase (5α-R) or to the active estrogen 17β-estradiol (E2) via the aromatase enzyme. Using male and female human pancreas sections, we show that the 5α-R type 1 isoform (SRD5A1) and aromatase are expressed in male and female β-cells. We show that cultured male and female human islets exposed to T produce DHT and downstream metabolites. In these islets, exposure to the 5α-R inhibitors finasteride and dutasteride inhibited T conversion into DHT. We did not detect T conversion into E2 from female islets. However, we detected T conversion into E2 in islets from two out of four male donors. In these donors, exposure to the aromatase inhibitor anastrozole inhibited E2 production. Notably, in cultured male and female islets, T enhanced glucose-stimulated insulin secretion (GSIS). In these islets, exposure to 5α-R inhibitors or the aromatase inhibitor both inhibited T enhancement of GSIS. In conclusion, male and female human islets convert T into DHT and E2 via the intracrine activities of SRD5A1 and aromatase. This process is necessary for T enhancement of GSIS.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Aromatase; Cells, Cultured; Female; Gene Expression Regulation, Enzymologic; Humans; Insulin; Insulin-Secreting Cells; Male; Testosterone
PubMed: 32855171
DOI: 10.2337/db20-0228 -
International Journal of Molecular... Aug 2020Aromatase inhibitors (AIs) have radically changed the prognosis of hormone receptor positive breast cancer (BC) in post-menopausal women, and are a mainstay of the... (Review)
Review
Aromatase inhibitors (AIs) have radically changed the prognosis of hormone receptor positive breast cancer (BC) in post-menopausal women, and are a mainstay of the adjuvant therapy for BC after surgery in place of, or following, Tamoxifen. However, AIs aren't side effect-free; frequent adverse events involve the musculoskeletal system, in the form of bone loss, AI-associated arthralgia (AIA) syndrome and autoimmune rheumatic diseases. In this narrative review, we reported the main clinical features of these three detrimental conditions, their influence on therapy adherence, the possible underlying molecular mechanisms and the available pharmacological and non-pharmacological treatments. The best-known form is the AIs-induced osteoporosis, whose molecular pathway and therapeutic possibilities were extensively investigated in the last decade. AIA syndrome is a high prevalent joint pain disorder which often determines a premature discontinuation of the therapy. Several points still need to be clarified, as a universally accepted diagnostic definition, the pathogenetic mechanisms and satisfactory management strategies. The association of AIs therapy with autoimmune diseases is of the utmost interest. The related literature has been recently expanded, but many issues remain to be explored, the first being the molecular mechanisms.
Topics: Animals; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Estrogens; Female; Humans; Musculoskeletal Diseases
PubMed: 32781535
DOI: 10.3390/ijms21165625 -
Cellular and Molecular Life Sciences :... May 2022Although type I interferons (IFNs) play multifaceted roles during tumorigenesis and cancer treatment, the interplay between type I IFNs and estrogen signaling in breast...
Although type I interferons (IFNs) play multifaceted roles during tumorigenesis and cancer treatment, the interplay between type I IFNs and estrogen signaling in breast cancer (BC) microenvironment is not well understood. Here, we report a novel function of type I IFNs in inducing aromatase expression in adipose tissues surrounding BC, which potentiates the E-dependent growth of estrogen receptor (ER)-positive BC. First, we found that expression levels of type I IFNs correlate negatively with clinical outcome but positively with tumor grade in patients with ER-positive BC. Levels of type I IFNs were elevated in cocultured media of immune cells and BC cells, which increased aromatase expression and E production in Simpson-Golabi-Behmel syndrome preadipocytes. The type I IFN-induced aromatase expression was dependent on IFN-γ-inducible protein 16 (IFI16), which is encoded by an interferon-stimulated gene. At the molecular level, type I IFNs led to recruitment of HIF1α-IFI16-PRMT2 complex to the hypoxia-response element located in the aromatase PI.3/PII promoter. Next, we generated an adipocyte-specific Ifi204, which is a mouse ortholog of human IFI16, knockout mouse (Ifi204-AKO). IFNβ induced E production in the preadipocytes isolated from the control mice, but such E production was far lower in the Ifi204-AKO preadipocytes. Importantly, the growth of orthotopically inoculated E0771 ER-positive mammary tumors was reduced significantly in the Ifi204-AKO mice. Taken together, our findings provide novel insights into the crosstalk between type I IFNs and estrogen signaling in the progression of ER-positive BC.
Topics: Adipocytes; Animals; Aromatase; Breast; Breast Neoplasms; Estrogens; Female; Humans; Interferon Type I; Mice; Nuclear Proteins; Phosphoproteins; Tumor Microenvironment
PubMed: 35593921
DOI: 10.1007/s00018-022-04333-y -
The Oncologist Oct 2023Disparities in survival and clinical outcomes between African American and White patients with breast cancer (BC) are well documented, but African American patients have...
BACKGROUND
Disparities in survival and clinical outcomes between African American and White patients with breast cancer (BC) are well documented, but African American patients have not been well represented in randomized clinical trials of CDK4/6 inhibitors. Real-world studies can provide evidence for effective treatment strategies for underreported patient populations.
PATIENTS AND METHODS
This retrospective analysis of African American patients with HR+/HER2- metastatic breast cancer (mBC) from the Flatiron Health longitudinal database evaluated treatments for patients with BC in routine clinical practice in the US. Patients initiated first-line therapy with palbociclib plus an aromatase inhibitor (AI) or AI alone between February 2015 and March 2020. Outcomes assessed included overall survival (OS) and real-world progression-free survival (rwPFS) until September 2020.
RESULTS
Of 270 eligible patients, 127 (median age 64 years) were treated with palbociclib + AI, and 143 (median age 68 years) were treated with an AI. Median follow-up was 24.0 months for palbociclib + AI and 18.2 months for AI-treated patients. Median OS was not reached (NR; 95% CI, 38.2-NR) in the palbociclib + AI group versus 28.2 months (95% CI, 19.2-52.8) in the AI group (adjusted HR, 0.56; 95% CI, 0.36-0.89; P = .013). Median rwPFS was 18.0 months (95% CI, 12.4-26.7) in the palbociclib + AI group and 10.5 months (95% CI, 7.0-13.4) in the AI group (adjusted HR, 0.74; 95% CI, 0.47-1.17; P = .199).
CONCLUSION
This comparative analysis of palbociclib + AI versus AI alone indicates that palbociclib combined with endocrine therapy in the first line is associated with improved effectiveness for African American patients with HR+/HER2- mBC in real-world settings.
TRIAL NUMBER
NCT05361655.
Topics: Aged; Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Black or African American; Breast Neoplasms; Receptor, ErbB-2; Retrospective Studies
PubMed: 37487056
DOI: 10.1093/oncolo/oyad209 -
International Journal of Molecular... Jan 2021Breast cancer is the most common type of cancer. In the developmental stages of breast cancer, estrogens are strongly involved. As estrogen synthesis is regulated by the... (Review)
Review
Breast cancer is the most common type of cancer. In the developmental stages of breast cancer, estrogens are strongly involved. As estrogen synthesis is regulated by the enzyme aromatase, targeting the activity of this enzyme represents a therapeutic option. The pineal hormone melatonin may exert a suppressive role on aromatase activity, leading to reduced estrogen biosynthesis. A melatonin-mediated decrease in the expression of aromatase promoters and associated genes would provide suitable evidence of this molecule's efficacy as an aromatase inhibitor. Furthermore, melatonin intensifies radiation-induced anti-aromatase effects and counteracts the unwanted disadvantages of chemotherapeutic agents. In this manner, this review summarizes the inhibitory role of melatonin in aromatase action, suggesting its role as a possible oncostatic molecule in breast cancer.
Topics: Animals; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Central Nervous System Depressants; Female; Humans; Melatonin
PubMed: 33406787
DOI: 10.3390/ijms22010438 -
Current Oncology (Toronto, Ont.) Jul 2021Non-compliance and non-persistence with endocrine therapy for breast cancer is common and usually related to treatment-induced side effects. There are anecdotal reports... (Review)
Review
BACKGROUND
Non-compliance and non-persistence with endocrine therapy for breast cancer is common and usually related to treatment-induced side effects. There are anecdotal reports that simply changing the time of day when taking endocrine therapy (i.e., changing morning dosing to evening dosing or vice versa) can reduce side effects.
LITERATURE REVIEW
We conducted a literature review to evaluate whether changing the timing of tamoxifen and/or aromatase inhibitor administration impacted patient outcomes. No randomized control trials or prospective cohort studies that looked at time of day of endocrine therapy were identified through our review of literature from 1947 until August 2020.
CONCLUSIONS
Given the rates of endocrine therapy non-compliance and non-persistence reported in the literature, ranging from 41-72% and 31-73%, respectively, simply changing the time of day when medications are taken could be an important strategy. We could identify no trials evaluating the effect of changes in timing of administration of endocrine therapy on breast cancer patient outcomes. Randomized control trials are clearly indicated for this simple and cost-effective intervention.
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Prospective Studies; Tamoxifen
PubMed: 34287262
DOI: 10.3390/curroncol28040229 -
Molecules (Basel, Switzerland) Mar 2023CDK4/6 and aromatase are prominent targets for breast cancer drug discovery and are involved in abnormal cell proliferation and growth. Although aromatase inhibitors...
CDK4/6 and aromatase are prominent targets for breast cancer drug discovery and are involved in abnormal cell proliferation and growth. Although aromatase inhibitors have proven to be effective (for example exemestane, anastrozole, letrozole), resistance to treatment eventually occurs through the activation of alternative signaling pathways, thus evading the antiproliferative effects of aromatase inhibitors. One of the evasion pathways is Cylin D-CDK4/6-Rb signaling that promotes tumor proliferation and resistance to aromatase inhibitors. There is significant evidence that the sequential inhibition of both proteins provides therapeutic benefits over the inhibition of one target. The basis of this study objective is the identification of molecules that are likely to inhibit both CDK4/6 and aromatase by computational chemistry techniques, which need further biochemical studies to confirm. Initially, a structure-based pharmacophore model was constructed for each target to screen the sc-PDB database. Consequently, pharmacophore screening and molecular docking were performed to evaluate the potential lead candidates that effectively mapped both of the target pharmacophore models. Considering abemaciclib (CDK4/6 inhibitor) and exemestane (aromatase inhibitor) as reference drugs, four potential virtual hit candidates (1, 2, 3, and 4) were selected based on their fit values and binding interaction after screening a sc-PDB database. Further, molecular dynamics simulation studies solidify the stability of the lead candidate complexes. In addition, ADMET and DFT calculations bolster the lead candidates. Hence, these combined computational approaches will provide a better therapeutic potential for developing CDK4/6-aromatase dual inhibitors for HR+ breast cancer therapy.
Topics: Humans; Female; Aromatase Inhibitors; Aromatase; Molecular Docking Simulation; Anastrozole; Breast Neoplasms; Molecular Dynamics Simulation; Enzyme Inhibitors; Cyclin-Dependent Kinase 4
PubMed: 36985460
DOI: 10.3390/molecules28062490 -
Acta Endocrinologica (Bucharest,... 2020Aromatase is a key enzyme in local estrogen production by androgen conversion, especially in women post-menopause. There have been controversies concerning aromatase...
CONTEXT
Aromatase is a key enzyme in local estrogen production by androgen conversion, especially in women post-menopause. There have been controversies concerning aromatase localization in breast carcinomas and its association with current histopathological variables.
MATERIAL AND METHODS
Using polyclonal antibody immunohistochemistry we assessed (by intensity and percentage scores) the immunolocalization of aromatase in 70 tissue samples, and described particularities within the molecular subtypes of breast cancer.
RESULTS
Aromatase was found in all tissue compartments: tumor (95.7%), stroma (58.6%) and adipose tissue (94.3%). Aromatase expression in tumor cells correlated inversely with tumor grading (p=-0.361, p=0.027), and positively with estrogen receptor status (ER, p=0.143, p<0.001). Dividing the study group by intrinsic subtypes, a strongly inversely association between tumor aromatase and grading (p=-0.486, p<0.001), and between stromal aromatase and Ki67-index (p=-0.448, p=0.048) was observed in luminal A breast cancer. Tumor aromatase and ER percentage scores had stronger correlations in luminal B HER2 negative (p=0.632, p=0.002), and positive (p=0.324, p=0.026) tumors. In contrast, in triple negative tumors, a positive association stromal aromatase and Ki67 index (p=-0.359, p=0.007) was observed.
CONCLUSION
Local aromatase was linked to better tumor differentiation and proliferation in luminal breast subtypes, and not in triple negative cases, suggesting a potential prognostic role of aromatase in breast carcinomas.
PubMed: 32685034
DOI: 10.4183/aeb.2020.22