RESUMO
Progesterone receptor antagonism is gaining attention due to progesterone's recognized role as a major mitogen in breast tissue. Limited but promising data suggest the potential efficacy of antiprogestins in breast cancer prevention. The present study presents secondary outcomes from a randomized controlled trial and examines changes in breast mRNA expression following mifepristone treatment in healthy premenopausal women. We analyzed 32 paired breast biopsies from 16 women at baseline and after two months of mifepristone treatment. In total, 27 differentially expressed genes were identified, with enriched biological functions related to extracellular matrix remodeling. Notably, the altered gene signature induced by mifepristone in vivo was rather similar to the in vitro signature. Furthermore, this gene expression signature was linked to breast carcinogenesis and notably linked with progesterone receptor expression status in breast cancer, as validated in The Cancer Genome Atlas dataset using the R2 platform. The present study is the first to explore the breast transcriptome following mifepristone treatment in normal breast tissue in vivo, enhancing the understanding of progesterone receptor antagonism and its potential protective effect against breast cancer.
Assuntos
Neoplasias da Mama , Mifepristona , Pré-Menopausa , Receptores de Progesterona , Transcriptoma , Humanos , Feminino , Receptores de Progesterona/metabolismo , Receptores de Progesterona/genética , Mifepristona/farmacologia , Mifepristona/uso terapêutico , Transcriptoma/efeitos dos fármacos , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Mama/metabolismo , Mama/efeitos dos fármacos , Mama/patologia , Perfilação da Expressão GênicaRESUMO
Whether trace metals modify breast density, the strongest predictor for breast cancer, during critical developmental stages such as puberty remains understudied. Our study prospectively evaluated the association between trace metals at Tanner breast stage B1 (n = 291) and at stages both B1 and B4 (n = 253) and breast density at 2 years post-menarche among Chilean girls from the Growth and Obesity Cohort Study. Dual-energy x-ray absorptiometry assessed the volume of dense breast tissue (absolute fibroglandular volume [FGV]) and percent breast density (%FGV). Urine trace metals included arsenic, barium, cadmium, cobalt, cesium, copper, magnesium, manganese, molybdenum, nickel, lead, antimony, selenium, tin, thallium, vanadium, and zinc. At B1, a doubling of thallium concentration resulted in 13.69 cm3 increase in absolute FGV (ß: 13.69, 95% confidence interval [CI]: 2.81, 24.52), while a doubling of lead concentration resulted in a 7.76 cm3 decrease in absolute FGV (ß: -7.76, 95%CI: -14.71, -0.73). At B4, a doubling of barium concentration was associated with a 10.06 cm3 increase (ß: 10.06, 95% CI: 1.44, 18.60), copper concentration with a 12.29 cm3 increase (ß: 12.29, 95% CI: 2.78, 21.56), lead concentration with a 9.86 cm3 increase (ß: 9.86, 95% CI: 0.73, 18.98), antimony concentration with a 12.97 cm3 increase (ß: 12.97, 95% CI: 1.98, 23.79) and vanadium concentration with a 13.14 cm3 increase in absolute FGV (ß: 13.14, 95% CI: 2.73, 23.58). Trace metals may affect pubertal breast density at varying developmental stages with implications for increased susceptibility for breast cancer.
Assuntos
Absorciometria de Fóton , Densidade da Mama , Oligoelementos , Humanos , Feminino , Chile/epidemiologia , Adolescente , Densidade da Mama/efeitos dos fármacos , Oligoelementos/análise , Oligoelementos/urina , Estudos Prospectivos , Criança , Mama/efeitos dos fármacos , Mama/crescimento & desenvolvimento , Neoplasias da Mama/epidemiologiaRESUMO
Tamoxifen prevents recurrence of breast cancer and is also approved for preventive, risk-reducing, therapy. Tamoxifen alters the breast tissue composition and decreases the mammographic density. We aimed to test if baseline breast tissue composition influences tamoxifen-associated density change. This biopsy-based study included 83 participants randomised to 6 months daily intake of placebo, 20, 10, 5, 2.5, or 1 mg tamoxifen. The study is nested within the double-blinded tamoxifen dose-determination trial Karolinska Mammography Project for Risk Prediction of Breast Cancer Intervention (KARISMA) Study. Ultrasound-guided core-needle breast biopsies were collected at baseline before starting treatment. Biopsies were quantified for epithelial, stromal, and adipose distributions, and epithelial and stromal expression of proliferation marker Ki67, oestrogen receptor (ER) and progesterone receptor (PR). Mammographic density was measured using STRATUS. We found that greater mammographic density at baseline was positively associated with stromal area and inversely associated with adipose area and stromal expression of ER. Premenopausal women had greater mammographic density and epithelial tissue, and expressed more epithelial Ki67, PR, and stromal PR, compared to postmenopausal women. In women treated with tamoxifen (1-20 mg), greater density decrease was associated with higher baseline density, epithelial Ki67, and stromal PR. Women who responded to tamoxifen with a density decrease had on average 17% higher baseline density and a 2.2-fold higher PR expression compared to non-responders. Our results indicate that features in the normal breast tissue before tamoxifen exposure influences the tamoxifen-associated density decrease, and that the age-associated difference in density change may be related to age-dependant differences in expression of Ki67 and PR.
Assuntos
Antineoplásicos Hormonais , Densidade da Mama , Neoplasias da Mama , Mamografia , Tamoxifeno , Humanos , Tamoxifeno/farmacologia , Tamoxifeno/administração & dosagem , Feminino , Densidade da Mama/efeitos dos fármacos , Pessoa de Meia-Idade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Mamografia/métodos , Adulto , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Método Duplo-Cego , Receptores de Estrogênio/metabolismo , Idoso , Receptores de Progesterona/metabolismo , Mama/efeitos dos fármacos , Mama/diagnóstico por imagem , Mama/patologia , Mama/metabolismo , Antígeno Ki-67/metabolismo , Antígeno Ki-67/análise , Pós-MenopausaRESUMO
Population studies show worrisome trends towards earlier breast development, difficulty in breastfeeding, and increasing rates of breast cancer in young women. Multiple epidemiological studies have linked these outcomes with chemical exposures, and experimental studies have shown that many of these chemicals generate similar effects in rodents, often by disrupting hormonal regulation. These endocrine-disrupting chemicals (EDCs) can alter the progression of mammary gland (MG) development, impair the ability to nourish offspring via lactation, increase mammary tissue density, and increase the propensity to develop cancer. However, current toxicological approaches to measuring the effects of chemical exposures on the MG are often inadequate to detect these effects, impairing our ability to identify exposures harmful to the breast and limiting opportunities for prevention. This paper describes key adverse outcomes for the MG, including impaired lactation, altered pubertal development, altered morphology (such as increased mammographic density), and cancer. It also summarizes evidence from humans and rodent models for exposures associated with these effects. We also review current toxicological practices for evaluating MG effects, highlight limitations of current methods, summarize debates related to how effects are interpreted in risk assessment, and make recommendations to strengthen assessment approaches. Increasing the rigor of MG assessment would improve our ability to identify chemicals of concern, regulate those chemicals based on their effects, and prevent exposures and associated adverse health effects.
Assuntos
Neoplasias da Mama , Mama , Exposição Ambiental , Poluentes Ambientais , Feminino , Humanos , Animais , Neoplasias da Mama/induzido quimicamente , Mama/efeitos dos fármacos , Mama/crescimento & desenvolvimento , Exposição Ambiental/efeitos adversos , Densidade da Mama/efeitos dos fármacos , Puberdade/efeitos dos fármacos , Poluentes Ambientais/farmacologiaRESUMO
BACKGROUND: The Breast Reconstruction Evaluation of Acellular Dermal Matrix as a Sling Trial is a single-center, blinded, prospective, randomized, controlled trial established to compare outcomes using two popular types of acellular dermal matrices, AlloDerm and DermaMatrix, in tissue expander breast reconstruction. This study used the acellular dermal matrix biopsy specimens from the trial to evaluate how adjuvant therapy influences inflammation, neovascularization, and capsule formation of the acellular dermal matrix. METHODS: Punch biopsy specimens were taken at the time of expander exchange and were analyzed by a blinded pathologist. The inflammatory response was quantified by the number of fibroblasts, giant cells, and lymphocytes. Neovascularization and capsule formation were similarly quantified by the number of new capillaries and capsule presence and thickness, respectively. RESULTS: Histology specimens were collected from 109 patients (170 breasts). In the absence of adjuvant therapy, there was no significant difference between AlloDerm and DermaMatrix in terms of inflammation, neovascularization, or capsule thickness. Both acellular dermal matrices showed a significant decrease in inflammation and neovascularization with adjuvant therapy. When chemotherapy and radiation therapy were used, the decrease in inflammation was greatest for the group reconstructed with DermaMatrix (p < 0.039). CONCLUSIONS: Adjuvant therapy influences the inflammatory response, neovascularization, and capsule formation in both acellular dermal matrices. Adjuvant therapy has a protective effect on the inflammatory response toward both acellular dermal matrices in breast reconstruction. In the setting of chemotherapy and radiation therapy, DermaMatrix produced the greatest reduction in inflammation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.
Assuntos
Derme Acelular , Mama/patologia , Quimiorradioterapia Adjuvante , Inflamação/patologia , Mamoplastia/métodos , Neovascularização Patológica/patologia , Complicações Pós-Operatórias/patologia , Antineoplásicos/farmacologia , Biópsia , Mama/efeitos dos fármacos , Mama/efeitos da radiação , Mama/cirurgia , Feminino , Seguimentos , Humanos , Inflamação/diagnóstico , Inflamação/etiologia , Inflamação/prevenção & controle , Neovascularização Patológica/diagnóstico , Neovascularização Patológica/etiologia , Neovascularização Patológica/prevenção & controle , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Método Simples-Cego , Expansão de Tecido/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Kolaviron (KV) is a flavonoid-rich portion obtained from Garcinia kola seeds with a number of reported pharmacological effects. However, its ameliorative effects on 7,12-Dimethylbenzanthracene (DMBA)-induced mammary damage has not been fully investigated, despite the reported use of the seeds in the treatment of inflammatory related disorders. OBJECTIVE: To evaluate the ameliorative effects of KV on DMBA-induced mammary damage in female Wistar rats. METHODS: Forty-nine (49) female Wistar rats were randomly assigned into seven groups of seven rats each. DMBA was administered orally to rats in five of the groups as a single dose of 80 mg/kg body wt while the remaining two groups received the vehicle. The rats were palpated weekly for 3 months to monitor tumor formation. After 3 months of DMBA administration, 1 ml of blood was collected to assay for estrogen receptor- α (ER-α) level. Thereafter, the vehicle (dimethyl sulfoxide) was daily administered to the negative control and positive control groups for the 14 days duration of the experiment while three groups were each given a daily oral dose of 50, 100, and 200 mg/kg body wt of KV for the duration of the experiment. The last DMBA-induced group received 10 mg/kg body wt of the standard drug tamoxifen twice a week, and the remaining DMBA-free group received 200 mg/kg body wt KV. Subsequently, the animals were humanely sacrificed, and ER-α, sialic acids, sialidase, sialyltransferase levels were assayed in blood and mammary tissues followed by histopathological examinations. RESULTS: Significantly higher levels of estrogen receptor-α (ER-α), formation of lobular neoplastic cells, epithelial hyperplasia, lymphocyte infiltration, and increased sialylation were detected in DMBA-induced rats. Treatment with KV at 50, 100, and 200 mg/kg body weight resulted in a significant (p<0.05) decrease in ER-α level, free serum sialic acid (21.1%), the total sialic acid level of the mammary tissue (21.57%), sialyltransferase activity (30.83%) as well as mRNA level of the sialyltransferase gene (ST3Gal1) were observed after KV interventions. CONCLUSION: The findings suggest that KV could be further explored in targeting DMBA-induced mammary damage implicated in mammary carcinogenesis.
Assuntos
9,10-Dimetil-1,2-benzantraceno/antagonistas & inibidores , Mama/efeitos dos fármacos , Flavonoides/farmacologia , 9,10-Dimetil-1,2-benzantraceno/administração & dosagem , 9,10-Dimetil-1,2-benzantraceno/efeitos adversos , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Mama/patologia , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/sangue , Feminino , Flavonoides/administração & dosagem , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
In our previous research showed that tramadol having potential anti-tumor effect was associated with enhancement of oncological prognosis in patients with breast cancer surgery. As these effects have not been confirmed by clinical dose-regulated animal or prospective human studies, we investigated the anti-tumor effect of tramadol in vivo. Female nude mice orthotopically inoculated with luciferase-expressing MCF-7 cells, were randomly divided into the control (saline), tramadol group 1 (1.5 mg kg-1 day-1), tramadol group 2 (3 mg kg-1 day-1), and morphine (0.5 mg kg-1 day-1) (n = 5/group). Bioluminescence signals after D-luciferin injection, tumor size, and tumor weight were compared among groups after 4 weeks. Estrogen receptor (ER), progesterone receptor (PR), and transient receptor potential vanilloid (TRPV)-1 expression, natural killer (NK) cell activity, and serum interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-6 were then examined. Tumour growth was attenuated in tramadol-treated groups (P < 0.05). NK cell activity was significantly decreased only in the morphine treated group not in sham, control, and tramadol groups. The expression levels of ERα, PRα and ß, and TRPV1 were decreased in tramadol group 2 compared with those in the morphine group, but not compared to the control group. Serum levels of IL-6 and TNFα were reduced in both tramadol-treated group 1 and 2 compared to the control group. Overall, clinical dose of tramadol has anti-tumour effects on MCF-7 cell-derived breast cancer in a xenograft mouse model.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Xenoenxertos/efeitos dos fármacos , Tramadol/farmacologia , Animais , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Morfina/farmacologia , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Canais de Cátion TRPV/metabolismo , Transplante Heterólogo/métodosRESUMO
Breast cancer is one of the most reported cancers that can lead to death. Despite the advances in diagnosis and treatment procedures, the possibility of cancer recurrences is still high in many cases. With that in consideration, researchers from all over the world are showing interest in the unique features of Graphene oxide (GO), such as its excellent and versatile physicochemical properties, to explore further its potential and benefits towards breast cancer cell treatment. In this study, the cell viability and electrical response of GO, in terms of resistivity and impedance towards the breast cancer cells (MCF7) and normal breast cells (MCF10a), were investigated by varying the pH and concentration of GO. Firstly, the numbers of MCF7 and MCF10a were measured after being treated with GO for 24 and 48 h. Next, the electrical responses of these cells were evaluated by using interdigitated gold electrodes (IDEs) that are connected to an LCR meter. Based on the results obtained, as the pH of GO increased from pH 5 to pH 7, the number of viable MCF7 cells decreased while the number of viable MCF10a slightly increased after the incubation period of 48 h. Similarly, the MCF7 also experienced higher cytotoxicity effects when treated with GO concentrations of more than 25 µg/mL. The findings from the electrical characterization of the cells observed that the number of viable cells has corresponded to the impedance of the cells. The electrical impedance of MCF7 decreased as the number of highly insulating viable cell membranes decreased. But in contrast, the electrical impedance of MCF10a increased as the number of highly insulating viable cell membranes increased. Hence, it can be deduced that the GO with higher pH and concentration influence the MCF7 cancer cell line and MCF10a normal breast cell.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Grafite/farmacologia , Apoptose/efeitos dos fármacos , Mama/efeitos dos fármacos , Contagem de Células , Linhagem Celular Tumoral , Impedância Elétrica/uso terapêutico , Eletrodos , Feminino , Ouro/farmacologia , Humanos , Células MCF-7 , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
Gender-affirming hormone therapy (GAHT) is often provided to transgender people. In this review of the literature, the current knowledge of ovarian, breast, and metabolic changes (body composition, insulin resistance, bone density, cardiovascular risk factors such as lipids, blood pressure, and hematocrit) observed following GAHT in adult transgender men is discussed. A body of literature concurs to describe that long-term androgen therapy in transgender men exerts atrophic effects on the breast. There is currently no evidence of an increased risk of breast cancer. Long-term testosterone treatment induces ovarian effects that become visible after 6 months of therapy. These changes consist of both macroscopic and microscopic alterations of ovarian morphology that mimic the typical ovarian aspect encountered in women with polycystic ovary syndrome but without an effect on antral follicle count. Metabolic effects of long-term androgen treatment in transgender men put them at par with cisgender men in terms of lipid profile, insulin resistance, and overall mortality. Body composition changes as desired after testosterone administration in most transgender men, and insulin resistance decreases with virilization. There are no detrimental effects on bone mineral density. Cardiometabolic risk and morbidity data are currently reassuring, even if certain studies show conflicting results. An increase in blood pressure and a decrease in high-density lipoprotein cholesterol have been reported as risk factors, whereas polycythemia is rare and treatable. Most available data are observational and based on biochemical markers instead of the more direct measures of cardiovascular damage. An explanation for these observed changes is mostly lacking. Psychological stress and lifestyle factors are often forgotten in a much needed integrated approach.
Assuntos
Androgênios/uso terapêutico , Mama/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ovário/efeitos dos fármacos , Procedimentos de Readequação Sexual , Testosterona/uso terapêutico , Pessoas Transgênero , Transexualidade/cirurgia , Androgênios/efeitos adversos , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Feminino , Disforia de Gênero/psicologia , Identidade de Gênero , Humanos , Resistência à Insulina , Masculino , Ovário/metabolismo , Ovário/patologia , Fatores de Risco , Procedimentos de Readequação Sexual/efeitos adversos , Testosterona/efeitos adversos , Fatores de Tempo , Pessoas Transgênero/psicologia , Transexualidade/fisiopatologia , Transexualidade/psicologia , Resultado do TratamentoRESUMO
Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours' samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.
Assuntos
Adenomioepitelioma/genética , Neoplasias da Mama/genética , Mutação Puntual , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenomioepitelioma/tratamento farmacológico , Adenomioepitelioma/patologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imidazóis/uso terapêutico , Pessoa de Meia-Idade , Oximas/uso terapêutico , Mutação Puntual/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêuticoRESUMO
A convenient and selective approach to 13,17-secoestra-1,3,5(10)-trien-17-oic acid hydrazides and their N'-(het)arylmethylene derivatives was disclosed and these novel types of secosteroids were screened for cytotoxicity against hormone-dependent human breast cancer cell line MCF-7. A number of 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-(het)arylmethylene]hydrazides show significant cytotoxic effect comparable or superior to that for reference drug cisplatin. Compound 3l exhibits the highest activity with the IC50 value of about 2 µM and is 2.8 times more active than cisplatin. Hit 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-(het)arylmethylene]hydrazides 3d, 3l and 3q are characterized by high cytotoxicity and good selectivity towards MCF-7 breast cancer cells. The synthesized secosteroids may be considered as new promising antitumor agents.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Hidrazinas/química , Antibacterianos/farmacologia , Mama/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica/métodos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração Inibidora 50 , Lactonas/química , Células MCF-7 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Esteroides/química , Relação Estrutura-AtividadeRESUMO
Full term pregnancy at an early age is the only factor known to consistently protect against breast cancer. Because hormone receptor positive progenitors in the human breast relay endocrine signaling, we here sought to determine whether an experimental mimicry of the third trimester surge of hormones would change their susceptibility to growth stimulation. Hormone receptor positive, reduction mammoplasty-derived human breast epithelial progenitors were exposed to a short-term, pregnancy-level of estradiol, and their subsequent response to estradiol stimulation was analyzed. Exposure to pregnancy-level of estradiol results in subsequent lower sensitivity to estrogen-induced proliferation. Expression array and immunoblotting reveal upregulation of S100A7 and down-regulation of p27, both associated with parity and epithelial differentiation. Notably, we find that the epithelial differentiation is accompanied by upregulation of E-cadherin and down-regulation of vimentin as well as by diminished migration and more mature luminal epithelial differentiation in a mouse transplantation model. Our findings are in support of a de-sensitization mechanism for pregnancy-induced prevention against breast cancer.
Assuntos
Mama/efeitos dos fármacos , Estradiol/farmacologia , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Animais , Mama/citologia , Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Estrogênios/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Gravidez , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Proteína A7 Ligante de Cálcio S100/genética , Proteína A7 Ligante de Cálcio S100/metabolismoRESUMO
OBJECTIVES: Inhibition of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, the rate rate-determining enzyme for the biogenesis of cholesterol is known to show antineoplastic effects. Therefore, this study investigates the in-silico HMG-CoA reductase (HMGCR)-inhibitory and in-vivo anti-lipidaemic/anticancer effects of carotenoids from Spondias mombin. METHODS: Carotenoids from S. mombin leaves were characterized with the aid of liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). The characterized phytochemicals were obtained from PubChem. They were docked into the orthosteric site of human HMGCR (Protein Data Bank code 1HW8) using AutoDock 4.0 suites. DMBA (7,12-dimethylbenz[a]anthracene) model of breast cancer was treated with the carotenoids extract from S. mombin (100 mg/kg and 200 mg/kg doses) to assess its anti-lipidaemic cum anticancer effects. KEY FINDINGS: Carotenoids from S. mombin; beta-carotene-15,15'-epoxide, astaxanthin and 7,7',8,8'-tetrahydro-ß-ß-carotene demonstrate HMGCR inhibition. They form hydrophobic interactions with key residues within the catalytic domain of HMGCR. The carotenoids extract exhibits anti-lipidaemic/anticancer effects, lowering serum triglyceride, LDL and cholesterol concentration. It increases HDL concentration and downregulates the expression of HMGR, AFP, CEACAM-3, BRCA-1 and HIF-1 mRNAs. CONCLUSION: Carotenoids from S. mombin demonstrate HMG-CoA reductase (HMGCR) inhibition, anti-lipidaemic, and anticancer effects. The inhibition of HMGCR by the carotenoids extract further poses it as a potential anti-hypercholesterolaemia compounds.
Assuntos
Anacardiaceae/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/metabolismo , Carotenoides/farmacologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipolipemiantes/farmacologia , Acil Coenzima A/metabolismo , Animais , Anticolesterolemiantes/análise , Anticolesterolemiantes/farmacologia , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/uso terapêutico , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/tratamento farmacológico , Carotenoides/análise , Regulação para Baixo , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hipolipemiantes/análise , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Simulação de Acoplamento Molecular , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos Wistar , Xantofilas/análise , Xantofilas/farmacologia , beta Caroteno/análise , beta Caroteno/farmacologiaRESUMO
The dynamic contrast-enhanced MR imaging plays a crucial role in evaluating the effectiveness of neoadjuvant chemotherapy (NAC) even since its early stage through the prediction of the final pathological complete response (pCR). In this study, we proposed a transfer learning approach to predict if a patient achieved pCR (pCR) or did not (non-pCR) by exploiting, separately or in combination, pre-treatment and early-treatment exams from I-SPY1 TRIAL public database. First, low-level features, i.e., related to local structure of the image, were automatically extracted by a pre-trained convolutional neural network (CNN) overcoming manual feature extraction. Next, an optimal set of most stable features was detected and then used to design an SVM classifier. A first subset of patients, called fine-tuning dataset (30 pCR; 78 non-pCR), was used to perform the optimal choice of features. A second subset not involved in the feature selection process was employed as an independent test (7 pCR; 19 non-pCR) to validate the model. By combining the optimal features extracted from both pre-treatment and early-treatment exams with some clinical features, i.e., ER, PgR, HER2 and molecular subtype, an accuracy of 91.4% and 92.3%, and an AUC value of 0.93 and 0.90, were returned on the fine-tuning dataset and the independent test, respectively. Overall, the low-level CNN features have an important role in the early evaluation of the NAC efficacy by predicting pCR. The proposed model represents a first effort towards the development of a clinical support tool for an early prediction of pCR to NAC.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Mama/diagnóstico por imagem , Imageamento por Ressonância Magnética , Adulto , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Feminino , Humanos , Aprendizado de Máquina , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Redes Neurais de Computação , Radiografia , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Resultado do TratamentoRESUMO
Clinical studies backed by research in animal models suggest that vitamin D may protect against the development of breast cancer, implicating vitamin D as a promising candidate for breast cancer prevention. However, despite clear preclinical evidence showing protective roles for vitamin D, broadly targeted clinical trials of vitamin D supplementation have yielded conflicting findings, highlighting the complexity of translating preclinical data to efficacy in humans. While vitamin D supplementation targeted to high-risk populations is a strategy anticipated to increase prevention efficacy, a complimentary approach is to target transient, developmental windows of elevated breast cancer risk. Postpartum mammary gland involution represents a developmental window of increased breast cancer promotion that may be poised for vitamin D supplementation. Targeting the window of involution with short-term vitamin D intervention may offer a simple, cost-effective approach for the prevention of breast cancers that develop postpartum. In this review, we highlight epidemiologic and preclinical studies linking vitamin D deficiency with breast cancer development. We discuss the underlying mechanisms through which vitamin D deficiency contributes to cancer development, with an emphasis on the anti-inflammatory activity of vitamin D. We also discuss current evidence for vitamin D as an immunotherapeutic agent and the potential for vitamin D as a preventative strategy for young woman's breast cancer.
Assuntos
Neoplasias da Mama/prevenção & controle , Vitamina D/administração & dosagem , Idade de Início , Animais , Mama/efeitos dos fármacos , Mama/fisiologia , Neoplasias da Mama/epidemiologia , Suplementos Nutricionais , Feminino , Humanos , Substâncias Protetoras/administração & dosagemRESUMO
Specific link between high fructose uptake and cancer development and progression highlighted fructose transporters as potential means to achieve GLUT-mediated discrimination between normal and cancer cells. The gained expression of fructose-specific transporter GLUT5 in various cancers offers a possibility for developing cancer-specific imaging and bioactive agents. Herein, we explore the feasibility of delivering a bioactive agent through cancer-relevant fructose-specific transporter GLUT5. We employed specific targeting of GLUT5 by 2,5-anhydro-D-mannitol and investigated several drug conjugates for their ability to induce cancer-specific cytotoxicity. The proof-of-concept analysis was carried out for conjugates of chlorambucil (CLB) in GLUT5-positive breast cancer cells and normal breast cells. The cytotoxicity of conjugates was assessed over 24 h and 48 h, and significant dependence between cancer-selectivity and conjugate size was observed. The differences were found to relate to the loss of GLUT5-mediated uptake upon increased conjugate size and hydrophobicity. The findings provide information on the substrate tolerance of GLUT5 and highlight the importance of maintaining appropriate hydrophilicity for GLUT-mediated delivery.
Assuntos
Neoplasias da Mama/patologia , Mama/citologia , Clorambucila/farmacologia , Transportador de Glucose Tipo 5/metabolismo , Manitol/análogos & derivados , Antineoplásicos Alquilantes/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Manitol/metabolismo , Especificidade por SubstratoRESUMO
BACKGROUND: Increased plasma aldehyde dehydrogenase 1 (ALDH1) levels have been proposed to predict cancer chemoresistance. However, studies have reported inconsistent results, depending on the type of cancer cells used. OBJECTIVE: This study aimed to investigate the correlation between plasma levels of ALDH1 and chemotherapy responses to the taxane-adriamycin-cyclophosphamide (TAC) regimen in breast cancer patients. METHODS: Thirty breast cancer patients who underwent chemotherapy using the TAC regimen were included in this study. Blood sampling was performed before chemotherapy was initiated and after the first and third cycles of chemotherapy administration. After 3 cycles of chemotherapy, patients were categorized as non-responsive if the tumor size was reduced <30%, if the tumor size remained the same or increased, or if any new tumors were discovered. Patients were defined as responsive after 3 cycles of chemotherapy if the tumor mass disappeared, if the tumor size was reduced by at least 30% of the initial size and if no new tumors were found. RESULTS: Among the 30 patients, only five were responsive to the TAC regimen. The clinical response to TAC was not correlated with the patient's age, cancer grading, or tumor stage. A change in the ALDH1 levels was observed after the third cycle of TAC administration, with significantly higher ALDH1 levels observed in responsive compared with non-responsive patients (p < 0.05). CONCLUSION: The results of this study may indicate a role for ALDH1 in chemoresponsiveness, rather than chemoresistance, for the TAC regimen in breast cancer patients. Further research remains necessary to confirm this result.
Assuntos
Família Aldeído Desidrogenase 1/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/uso terapêutico , Mama/efeitos dos fármacos , Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Congressos como Assunto , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Taxoides/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The increasing use of "kidney"-nourishing Traditional Chinese Medicine (TCM) like Er-xian decoction (EXD) for management of menopausal symptoms and osteoporosis has aroused concerns about their safety, and whether they interact with prescription drugs as both of them act via estrogen receptors (ERs) and regulate serum estradiol. AIM OF THE STUDY: The present study aimed to evaluate whether EXD selectively exerted estrogenic activities and interacted with Selective Estrogen Receptor Modulators (SERMs). MATERIALS AND METHODS: In vivo, mature ovariectomized (OVX) rats were administrated with EXD or combined treatment of EXD and SERMs for 12 weeks. The tissue-selective effect of EXD and its interaction of SERMs were studied in four estrogen sensitive tissues, bone, brain, breast and uterus. In vitro, the interaction of extracts of EXD-treated serum and SERMs in four ER-positive cell lines. RESULTS: In OVX rats, EXD selectively alleviated estrogen deficiency-induced changes in the bone and brain without inducing any estrogenic effects in the breast or uterus. Two-way ANOVA indicated the presence of interactions between EXD and SERMs in OVX rats but EXD did not significantly alter the tissue responses to SERMs in the bone, breast or brain. Indeed, the combined use of EXD and SERMs appeared to suppress the estrogenic effect of raloxifene and tamoxifen in the uterus. Extract of EXD-treated serum directly stimulated cell proliferation or differentiation in human osteosarcoma MG-63, neuroblastoma SHSY5Y, breast cancer MCF-7, and endometrial Ishikawa cells. Two-way ANOVA revealed that EXD-treated serum interacted with SERMs at various concentrations and altered the effects of tamoxifen in MG-63 and MCF-7 cells. CONCLUSIONS: EXD exerted estrogenic effects in a tissue-selective manner and interacted with SERMs. Combined treatment of EXD and SERMs did not hamper the beneficial effects of SERMs on the bone or brain but appeared to moderate the estrogenic effect of SERMs in the uterus.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Estrogênios/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Estradiol/farmacologia , Estradiol/uso terapêutico , Estrogênios/química , Estrogênios/uso terapêutico , Feminino , Interações Ervas-Drogas/fisiologia , Hormônios/sangue , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Medicina Tradicional Chinesa , Modelos Biológicos , Ovariectomia/efeitos adversos , Cloridrato de Raloxifeno/farmacologia , Cloridrato de Raloxifeno/uso terapêutico , Ratos Sprague-Dawley , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologia , ÁguaAssuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , COVID-19/complicações , Tamoxifeno/uso terapêutico , Mama/efeitos dos fármacos , Mama/virologia , Neoplasias da Mama/virologia , COVID-19/virologia , Sobreviventes de Câncer , Feminino , Humanos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/virologiaRESUMO
Hormone replacement therapy in menopause is used to improve climacteric syndrome in women whose quality of life is affected. However, given the wide variety of progestogens available, it is important to evaluate their differential benign changes (radiological, cellular, and clinical) on the breast. This review aimed to determine the different benign changes of progestogens used in postmenopausal combined hormone therapy on the breast (radiological, cellular, and clinical), in women without mammary pathology, in order to establish their safety profile. A systematic review of the literature was carried out with a balanced search strategy for the identification of relevant references in the MEDLINE, BVSalud, EMBASE, ProQuest, and Cochrane databases until November 2019. The search terms used were 'menopause' or 'hormonal replacement therapy' or 'progestins' or 'estrogen' or 'mastodynia' or 'benign breast disease' or 'mammography'. Data were collected from the 'eligible' articles by two researchers (ARF and SHA), and possible discrepancies in inclusion were resolved by consensus. A total of 1886 articles were identified; 60 full-text articles were reviewed, and 17 articles that met the inclusion criteria were included for the qualitative analysis. In conclusion, combined hormone replacement therapy is associated with benign effects on the breast, such as mastodynia and increased mammographic density.