RESUMEN
Plectranthus amboinicus leaves were subjected to hydrodistillation to obtain essential oil (EO). Phytochemical analysis using gas chromatography-mass spectrometry revealed a diverse range of compounds in the EO, with p-cymen-4-ol (18.57%) emerging as the most predominant, followed by isocaryophyllene (12.18%). The in vitro antiproliferative activity of EO against breast cancer was assessed in MCF-7 and MDA-MB-231 cell lines. The MTT assay results revealed that EO showed IC50 values of 42.25 µg/mL and 13.44 µg/mL in MCF-7 cells and 63.67 µg/mL and 26.58 µg/mL in MDA-MB-231 cells after 24 and 48 h, respectively. The in silico physicochemical and pharmacokinetic profiles of the EO constituents were within acceptable limits. Molecular docking was conducted to investigate the interactions between the constituents of the EO and protein Aromatase (PDB ID:3S79). Among the EO constituents, 4-tert-butyl-2-(5-tert-butyl-2-hydroxyphenyl)phenol (4BHP) exhibited the highest dock score of -6.580 kcal/mol when compared to the reference drug, Letrozole (-5.694 kcal/mol), but was slightly lesser than Anastrozole (-7.08 kcal/mol). Molecular dynamics simulation studies (100 ns) of the 4BHP complex were performed to study its stability patterns. The RMSD and RMSF values of the 4BHP protein complex were found to be 2.03 Å and 4.46 Å, respectively. The binding free energy calculations revealed that 4BHP displayed the highest negative binding energy of -43 kcal/mol with aromatase protein, compared to Anastrozole (-40.59 kcal/mol) and Letrozole (-44.54 kcal/mol). However, further research is required to determine the safety, efficacy, and mechanism of action of the volatile oil. Taking into consideration the key findings of the present work, the development of a formulation of essential oil remains a challenging task and novel drug delivery systems may lead to site-specific and targeted delivery for the effective treatment of breast cancer.
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Neoplasias de la Mama , Aceites Volátiles , Plectranthus , Humanos , Femenino , Aceites Volátiles/farmacología , Aceites Volátiles/análisis , Aceites Volátiles/química , Plectranthus/química , Plectranthus/metabolismo , Aromatasa/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Anastrozol/metabolismo , Letrozol/metabolismo , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: This study was designed to evaluate the effects of low-frequency electroacupuncture (EA) on glucose and lipid disturbances in a rat model of polycystic ovary syndrome (PCOS) characterized by insulin resistance (IR) and hepatic steatosis. METHODS: The PCOS rat model was induced by continuous administration of letrozole (LET) combined with a high-fat diet (HFD). Female Sprague-Dawley rats were divided into the following four groups: control, control + EA, LET + HFD and LET + HFD + EA. EA was administered five or six times a week with a maximum of 20 treatment sessions. Body weight, estrous cyclicity, hormonal status, glucose and insulin tolerance, lipid profiles, liver inflammation factors, liver morphology and changes in the phosphatidylinositol 3-kinase (PI3-K)/Akt (protein kinase B) pathway were evaluated. RESULTS: The rat model presented anovulatory cycles, increased body weight, elevated testosterone, abnormal glucose and lipid metabolism, IR, liver inflammation, hepatic steatosis and dysregulation of the insulin-mediated PI3-K/Akt signaling axis. EA reduced fasting blood glucose, fasting insulin, area under the curve for glucose, homeostasis model assessment of IR indices, triglycerides and free fatty acids, and alleviated hepatic steatosis. Furthermore, low-frequency EA downregulated mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6, upregulated mRNA expression of peroxisome proliferator-activated receptor (PPAR)-α, increased protein expression of phosphorylated (p)-Akt (Ser473), p-glycogen synthase kinase (GSK) 3ß (Ser9) and glucose transporter 4 (GLUT4), increased the ratio of p-GSK3ß to GSK3ß and downregulated protein expression of GSK3ß. CONCLUSION: An obese PCOS rat model with IR and hepatic steatosis was successfully established by the combination of LET and HFD. EA improved dysfunctional glucose and lipid metabolism in this PCOS-IR rat model, and the molecular mechanism appeared to involve regulation of the expression of key molecules of the PI3-K/Akt insulin signaling pathway in the liver.
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Electroacupuntura , Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Humanos , Ratas , Femenino , Animales , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Síndrome del Ovario Poliquístico/terapia , Síndrome del Ovario Poliquístico/metabolismo , Letrozol/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratas Sprague-Dawley , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hígado/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Glucosa/metabolismo , Peso Corporal , Fosfatidilinositol 3-Quinasa/metabolismo , Triglicéridos , Inflamación/metabolismo , ARN Mensajero/metabolismoRESUMEN
Polycystic ovary syndrome (PCOS) is a common endocrine disorder related to psychological distress. However, the mechanism underlying increased prevalence of depression in PCOS remained unclear. This study aimed to explore the unique transcriptional landscape of ovary and offered a platform to explore the mechanism of PCOS, as well as the influences caused by depression. The PCOS rat model was established by letrozole whereas PCOS rat model with depression was established by letrozole combined with chronic unpredicted mild stress (CUMS). Then single-cell RNA sequencing (scRNA-Seq) was applied to analyze the transcriptional features of rat ovaries. Granulosa cells (GCs) and fibroblasts (Fibros) accounted for the top two clusters of total 12 cell types. There were nine clusters in GCs, related to inflammatory response, endoplasmic reticulum (ER) stress, and steroidogenesis. The expression of differentially expressed genes (DEG) Hes1 was higher in PCOS and PCOS + CUMS groups, exhibiting enhanced expression by pseudotime and positively related to inflammation. Pseudotemporal analysis revealed that inflammation contributed to the different GCs distributions. Moreover, analysis of DEGs and gene ontology (GO) function enrichment revealed CUMS aggravated inflammation in PCOS GCs possibly via interferon signaling pathway. In theca cells (TCs), nine clusters were observed and some of them were relevant to inflammation, ER stress, and lipid metabolism. DEGs Ass1, Insl3, and Ifi27 were positively related to Cyp17a1, and Ces1d might contribute to the different trajectory of TCs. Subsequent scRNA-seq revealed a signature profile of endothelial cells (ECs) and Fibros, which suggest that inflammation-induced damage of ECs and Fibro, further exacerbated by CUMS. Finally, analysis of T cells and mononuclear phagocytes (MPs) revealed the existence of immune dysfunction, among which interferon signaling played a critical role. These findings provided more knowledge for a better understanding PCOS from the view of inflammation and identified new biomarkers and targets for the treatment of PCOS with psychological diseases.NEW & NOTEWORTHY In this study, we mapped the landscape of polycystic ovary syndrome (PCOS) ovary with rat model induced by letrozole and provided a novel insight into the molecular mechanism of PCOS accompanied by chronic unpredicted mild stress (CUMS) at single-cell transcriptomic level. These observations highlight the importance of inflammation in the pathogenesis of PCOS, which might also be the bridge between PCOS and psychological diseases.
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Síndrome del Ovario Poliquístico , Humanos , Femenino , Ratas , Animales , Síndrome del Ovario Poliquístico/metabolismo , Letrozol/efectos adversos , Letrozol/metabolismo , Células Endoteliales/metabolismo , Células de la Granulosa/metabolismo , Inflamación/genética , Inflamación/metabolismo , Interferones/efectos adversos , Interferones/metabolismoRESUMEN
Two distinct estrogen receptors (ERs) exist, ERα and ERß. Both receptors participate in sexual differentiation of the rat brain and likely participate in the regulation of adult sexual orientation (i.e. partner preference). This last idea was investigated herein by examining males treated with the aromatase inhibitor, letrozole, administered prenatally (0.56 µg/kg G10-22). This treatment usually provokes same-sex preference in 1-2 males per litter. Vehicle-treated males (with female preference) and females in spontaneous proestrus (with male preference) were included as controls. ERα and ERß expression was analyzed by immunohistochemistry in brain areas known to control masculine sexual behavior and partner preference, like the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BNST), medial amygdala (MeA) and ventromedial hypothalamic nucleus (VMH), as well as other brain regions suspected to participate in these processes. In addition, serum levels of estradiol were determined in all male groups. Letrozole-treated male rats that preferred sexually experienced males (LPM) showed over-expressed ERα in the hippocampal cornu Ammonis (CA 1, 3, 4) and dentate gyrus. The LPM group showed up-regulated ERß expression in the CA2 and reticular thalamic nucleus. The levels of estradiol did not differ between the groups. Higher expression of ERs in these males was different than their expression in females, with male sex-preference. This suggests that males with same-sex preference showed a unique brain, this sui generis steroid receptor expression probably participates in the biological underpinnings of sexual preference.
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Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Ratas , Animales , Femenino , Masculino , Humanos , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Letrozol/metabolismo , Receptores de Estrógenos/metabolismo , Encéfalo/metabolismo , Área Preóptica/metabolismo , Conducta Sexual , Estradiol/farmacología , Estradiol/metabolismoRESUMEN
Mounting literatures suggest that follicular fluid-derived exosomes (FF-Evs) influence the progression of progression of polycystic ovary syndrome (PCOS). The present study was designed to dissect the underlying mechanisms by which FF-Evs affect the PCOS. A rat model of PCOS was established using Letrozole induction. After treatment with FF-Evs, rats were examined for alterations in hormones, blood glucose, and lipid levels in serum, oestrus cycle, pathology in the ovaries, and apoptosis of ovarian cells. The functional rescue assays were performed to analyze the impact of long non-coding RNA 00092 (LINC00092) on PCOS rats. The cis-regulatory elements involved in the regulation of phosphatase and tensin homolog (PTEN) expression were analyzed using bioinformatic analysis, followed by verification of the mechanism. FF-Evs treatment ameliorated Letrozole-induced enhancement of weight, insulin resistance, dyslipidemia, and LH/FSH ratio, reduction of luteal cells, granulosa cells, and healthy follicles, prolonged oestrus, oestrous cycle arrest, ovarian tissue fibrosis, and ovarian cell apoptosis in rats, which were counteracted by treatment with shRNA targeting LINC00092. Regarding the mechanism, FF-Evs augmented LINC00092 expression in rats. LINC00092 bound to lysine demethylase 5 A (KDM5A), and KDM5A facilitated the demethylation of H3K4me3 to restrain the transcriptional activity of PTEN. Taken together, FF-Evs delivered LINC00092 repressed the transcriptional activity of PTEN by binding to KDM5A to enhance demethylation of H3K4me3, thereby reducing apoptosis in ovarian cells and alleviating PCOS symptoms.
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Síndrome del Ovario Poliquístico , ARN Largo no Codificante , Animales , Femenino , Ratas , Líquido Folicular/metabolismo , Letrozol/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Proteína 2 de Unión a Retinoblastoma/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Tensinas/metabolismoRESUMEN
BACKGROUND: Androgens are generally thought to cause prostate cancer, but the data from animal studies suggest that they must be aromatized to estrogen and act in concert with genotoxic estrogen metabolites. The objective of this study was to determine whether treatment with testosterone (T) combined with a nonestrogenic estrogen metabolite and a nongenotoxic estrogenic compound would all be necessary and sufficient for the induction of a high incidence of prostate cancer in the susceptible NBL rat strain. METHODS: NBL rats were treated with low-dose testosterone via slow-release Silastic implants and with the marginally estrogenic genotoxic catechol estrogen 4-hydroxyestradiol (4OH-E2) and the nongenotoxic estrogen 2-fluoroestradiol (2F-E2) and in one experiment the aromatase inhibitor letrozole via custom-made slow-release pellets. Animals were euthanized 52 weeks after implantation and their pituitaries and prostate complexes weighed and fixed in formalin. Hematoxylin and eosin (H&E)-stained step sections were prepared and examined microscopically for proliferative lesions. RESULTS: Animals treated with 2F-E2, with or without the other compounds, had enlarged pituitaries demonstrating its estrogenicity. Animals treated with T, with or without the other compounds, had enlarged prostates consistent with its androgenicity. Rats treated with T plus 2F-E2 and 4OH-E2 developed a high incidence of prostatic cancer (89%), while, surprisingly, rats treated with T plus only 2F-E2 also had a high incidence of prostate cancer (95%) contradicting our initial hypothesis. To test whether the formation of E2 from T by aromatase could lead to estrogen genotoxicity and prostate carcinogenesis we then rats treated with T and 2F-E2 also with letrozole and found that it reduced prostate cancer incidence by about 50%. CONCLUSIONS: These findings indicate that long-term treatment with a nongenotoxic estrogen (2F-E2) and T as well as uninhibited prostatic aromatase activity generating genotoxic E2 are all required for induction of a high incidence of prostatic adenocarcinomas in NBL rats. These and previous data indicate that androgen receptor-mediated action, estrogen receptor mediation, and estrogen genotoxicity are all required and sufficient for hormonal carcinogenesis in the NBL rat prostate. Interference with the estrogen genotoxicity is a potential approach to prostate cancer chemoprevention.
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Andrógenos , Neoplasias de la Próstata , Masculino , Humanos , Ratas , Animales , Andrógenos/metabolismo , Próstata/patología , Estradiol/metabolismo , Aromatasa/genética , Aromatasa/metabolismo , Letrozol/toxicidad , Letrozol/metabolismo , Estrógenos/farmacología , Neoplasias de la Próstata/patología , Testosterona/farmacología , Testosterona/metabolismo , Carcinogénesis/patología , Daño del ADNRESUMEN
PURPOSE: Polycystic ovary syndrome (PCOS) has a series of reproductive and metabolic consequences. Although the link between PCOS, IR, and obesity, their impact on the pathogenesis of PCOS has yet to be determined. Dysfunction of PI3K/AKT pathway has been reported as the main cause of IR in PCOS. This study purposed to explore the effects of selenium nanoparticles (SeNPs) alone and combined with metformin (MET) in a PCOS-IR rat model. METHODS: After 3 weeks of treatment with SeNPs and/or MET, biochemical analysis of glycemic & lipid profiles, and serum reproductive hormones was performed. Inflammatory, oxidative stress, and mitochondrial dysfunction markers were determined colormetrically. The expression of PI3K and Akt genes were evaluated by Real-time PCR. Histopathological examination and Immunohistochemical analysis of Ki-67 expression were performed. RESULTS: The results showed that treatment with SeNPs and/or MET significantly attenuated insulin sensitivity, lipid profile, sex hormones levels, inflammatory, oxidative stress and mitochondrial functions markers. Additionally, PI3K and Akt genes expression were significantly upregulated with improved ovarian histopathological changes. CONCLUSION: Combined SeNPs and MET therapy could be potential therapeutic agent for PCOS-IR model via modulation of the PI3K/Akt pathway, enhancing anti-inflammatory and anti-oxidant properties and altered mitochondrial functions.HighlightsThe strong relationship between obesity, insulin resistance, and polycystic ovarian syndrome.Disturbance of the PI3K/Akt signaling pathway is involved in the progression of polycystic ovary syndrome-insulin resistance (PCOS-IR).In PCOS-IR rats, combined SeNPs and metformin therapy considerably alleviated IR by acting on the PI3K/Akt signaling pathway.The combination of SeNPs and metformin clearly repaired ovarian polycystic pathogenesis and improved hormonal imbalance in PCOS-IR rats.
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Resistencia a la Insulina , Metformina , Nanopartículas , Síndrome del Ovario Poliquístico , Selenio , Femenino , Humanos , Ratas , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/metabolismo , Letrozol/metabolismo , Letrozol/farmacología , Letrozol/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Fosfatidilinositol 3-Quinasas/uso terapéutico , Selenio/uso terapéutico , Selenio/metabolismo , Selenio/farmacología , Metformina/uso terapéutico , Metformina/metabolismo , Metformina/farmacología , Transducción de Señal , Oxidación-Reducción , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Mitocondrias/metabolismo , LípidosRESUMEN
OBJECTIVES: Endocrine disorders in women of childbearing age, including polycystic ovarian syndrome (PCOS), have been linked to skeletal muscle insulin resistance with multiple post-receptor intracellular defects, disrupting metabolic flexibility. Short-chain fatty acids, such as acetate have been suggested as a metabolic modulator. However, the effects of acetate on aberrant metabolic switch in skeletal muscle of individuals with PCOS are unknown. This study therefore hypothesized that acetate would circumvent impaired metabolic switch in the skeletal muscle of a letrozole-induced PCOS rat model, probably by suppression of PDK4/NLRP3. METHODS: Eight-wk-old female Wistar rats were assigned into three groups (nâ¯=â¯6), which received vehicle, letrozole (1 mg/kg), and letrozole plus acetate (200 mg/kg), respectively. The administrations were done by oral gavage for 21 d. . RESULTS: Animals with PCOS had insulin resistance, increased testosterone, and leptin, as well as decreased adiponectin level. Additionally, the skeletal muscle was also characterized with increased lipid deposition, malondialdehyde, inflammatory mediators (nuclear factor-κB and tumor necrosis factor-α), lactate dehydrogenase, lactate/pyruvate ratio, HDAC and PDK 4 with corresponding decrease in glycogen synthesis, glutathione and NrF2. Besides, immunohistochemical evaluation showed severe expression of inflammasome and apoptosis in PCOS animals. Nonetheless, supplementation with acetate significantly attenuated these perturbations. CONCLUSIONS: The present results demonstrate aberrant metabolic switch in the skeletal muscle of PCOS animals, which is accompanied by excessive inflammation, oxidative stress and elevated levels of histone deacetylase and PDK4. The results suggested that histone deacetylase inhibitor, acetate circumvents impaired metabolic switch in the skeletal muscle of PCOS rats by suppression of PDK4/NLRP3 inflammasome.
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Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Humanos , Ratas , Femenino , Animales , Síndrome del Ovario Poliquístico/inducido químicamente , Letrozol/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Insulina/metabolismo , Ratas Wistar , Inflamasomas/metabolismo , Músculo Esquelético/metabolismo , Acetatos/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Topoisomerase TOP-IIA (TTOP-IIA) is widely used as a significant target for cancer therapeutics because of its involvement in cell proliferation. Steroidal drugs have been suggested for breast cancer treatment as aromatase enzymes inhibitors . TTOP-IIA inhibitors can be used as a target for the development of new cancer therapeutics. MATERIALS AND METHODS: In this study, we conducted a docking study on steroidal drugs Anastrozole (ANA), Letrozole (LET), and exemestane (EXE) with TTOP-IIA to explore the therapeutic area of these drugs. RESULTS: The binding interaction of EXE drug had significant docking interaction which is followed by ANA and LET. Thus, all these drugs could be used to inhibit the TTOP-IIA mediated cell proliferation and could be a hope to treat the other types of cancers. Among all three tested steroidal drugs, EXE showed binding energy -7.05 kcal/mol, hydrogen bond length1.78289 Å and amino acid involved in an interaction was A: LYS723:HZ3 -: UNK1:O6. CONCLUSION: The obtained data showed the most significant binding interaction analyzed with the tested enzyme. Thus, in vitro laboratory experimentation and in vivo research are necessary to put forward therapeutic repositioning of these drugs to establish them as a broad spectrum potential anticancer drugs.
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Antineoplásicos/química , Antineoplásicos/metabolismo , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/metabolismo , Anastrozol/química , Anastrozol/metabolismo , Androstadienos/química , Androstadienos/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Simulación por Computador , Femenino , Humanos , Letrozol/química , Letrozol/metabolismo , Conformación ProteicaRESUMEN
BACKGROUND Clinically, most patients of polycystic ovary syndrome (PCOS) also have insulin resistance (IR). The methods for establishing PCOS-IR animal model include using dehydroepiandrosterone (DHEA) and sodium prasterone sulfate subcutaneous injection, testosterone propionate combined with high-fat diet, and so on. This study aimed to establish an animal model of PCOS-IR using letrozole combined with a high fat diet. MATERIAL AND METHODS Study rats received 0.5% carboxymethylcellulose solution (CMC) or letrozole solution (1 mg/kg/day), with normal diet as control group and a high fat diet as the model group, for 21, 24, 27, and 30 days. The body weight and length were measured weekly. On Day 22, 25, 28 and 31, the weight, and the short and long diameters of the rat ovaries were measured, and blood samples were collected for the measurement of fasting plasma glucose (FPG), fasting insulin (FINS), triglyceride (TG), luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone (T). Ovarian tissue was collected for paraffin sectioning and hematoxylin and eosin (H&E) staining. RESULTS In model groups, rats' weight was significantly increased (P<0.05). On Day 28 and 31, the weight, Lee's index, and ovarian volume significantly increased compared with Day 22 (P<0.05). There were more dense transparent saclike follicles on the ovary surface under the microscope in model groups. Levels of LH/FSH, T, and TG were substantially increased (P<0.05), but levels of FINS and HOMA-IR were significantly increased (P<0.05) on Day 28 and 31 in the model groups. CONCLUSIONS This study implied that letrozole combined with a high fat diet for 27 days could induce the PCOS-IR rat model which has the characteristics of ovarian polycystic changes and endocrine and metabolic disorders.
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Resistencia a la Insulina/fisiología , Letrozol/farmacología , Síndrome del Ovario Poliquístico/fisiopatología , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Hormona Folículo Estimulante/sangre , Insulina/sangre , Letrozol/metabolismo , Hormona Luteinizante/sangre , Ovario/metabolismo , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/metabolismo , Ratas , Ratas Sprague-Dawley , Testosterona/sangreRESUMEN
Letrozole, a third-generation aromatase inhibitor, prevents the production of estrogens in the final step in conversion from androgens. Due to its efficacy at suppressing estrogens, letrozole has recently taken favor as a first-line adjuvant treatment for hormone-responsive breast cancer in middle-aged women. Though patient response to letrozole has generally been positive, there is conflicting evidence surrounding its effects on the development of depression. It is possible that the potential adverse effects of letrozole on mood are a result of the impact of hormonal fluctuations on neurogenesis in the hippocampus. Thus, to clarify the effects of letrozole on the hippocampus and behavior, we examined how chronic administration affects hippocampal neurogenesis and depressive-like behavior in middle-aged, intact female mice. Mice were given either letrozole (1 mg/kg) or vehicle by injection (i.p.) daily for 3 weeks. Depressive-like behavior was assessed during the last 3 days of treatment using the forced swim test, tail suspension test, and sucrose preference test. The production of new neurons was quantified using the immature neuronal marker doublecortin (DCX), and cell proliferation was quantified using the endogenous marker Ki67. We found that letrozole increased DCX and Ki67 expression and maturation in the dentate gyrus, but had no significant effect on depressive-like behavior. Our findings suggest that a reduction in estrogens in middle-aged females increases hippocampal neurogenesis without any adverse impact on depressive-like behavior; as such, this furthers our understanding of how estrogens modulate neurogenesis, and to the rationale for the utilization of letrozole in the clinical management of breast cancer.