RESUMO
Breast cancer has distinct causes and molecular characteristics at premenopausal and postmenopausal ages. The age-standardized incidence rate for postmenopausal breast cancer is more than 10 times higher than in premenopausal breast cancer. Here, we showed that the expression of 10 out of 20 most frequently mutated genes in breast cancer (namely, PIK3CA, CDH1, MUC16, PTEN, FAT3, FAT1, SPEN, ARID1A, LRP1B and RUNX1) is higher in premenopausal women with breast cancer than in postmenopausal women with breast cancer. The most significant differences in the expression in terms of menopause status were observed for RUNX1 and FAT1. Furthermore, we found that the majority of these 10 genes also show ER (estrogen receptor) or PR (progesterone receptor) status-dependent expression in both premenopausal and postmenopausal breast cancer patients. Unlike what we observed in the case of ER or PR status, the expression of most of these genes does not change depending on HER2 (human epidermal growth factor receptor 2) status in both premenopausal and postmenopausal breast cancer patients. Combined, our analysis suggests that menopause status might influence the expression of most frequently mutated genes in breast cancer, and that the most of these genes whose expression differ between pre- and post-menopausal women with breast cancer also show ER or PR status-dependent expression in women with breast cancer.
Assuntos
Neoplasias da Mama , Mutação , Pós-Menopausa , Pré-Menopausa , Humanos , Feminino , Neoplasias da Mama/genética , Pré-Menopausa/genética , Pós-Menopausa/genética , Pessoa de Meia-Idade , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Adulto , Regulação Neoplásica da Expressão Gênica , Idoso , Subunidade alfa 2 de Fator de Ligação ao Core/genéticaRESUMO
Sex hormones are known to interact with the immune system on multiple levels but information on the types of sex hormone receptors (SHR) and their expression levels in immune cells is scarce. Estrogen, testosterone and progesterone are all considered to interact with the immune system through their respective cell receptors (ERα and ERß including the splice variant ERß2, AR and PGR). In this study expression levels of SHR genes in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4+ and CD8+ T-cells, CD56+ NK-cells, CD14+ monocytes and CD19+ B-cells) were analyzed using standard manual qPCR or a qPCR array (TLDA). Nine healthy individuals including men (n = 2), premenopausal (Pre-MP, n = 5) and postmenopausal (post-MP, n = 2) women were sampled for PBMCs which were separated to cell subsets using FACS. Ten Pre-MP women were longitudinally sampled for total PBMCs at different phases of the menstrual cycle. We found that ERα was most abundant and, unexpectedly, that ERß2 was the dominant ERß variant in several FACS sorted cell subsets. In total PBMCs, SHR (ERα, ERß1, ERß2, and AR) expression did not fluctuate according to the phase of the menstrual cycle and PGR was not expressed. However, several immune response genes (GATA3, IFNG, IL1B, LTA, NFKB1, PDCD1, STAT3, STAT5A, TBX21, TGFB1, TNFA) were more expressed during the ovulatory and mid-luteal phases. Sex hormone levels did not correlate significantly with gene expression of SHR or immune response genes, but sex hormone-binding globulin (SHBG), a steroid hormone transporting protein, was positively correlated to expression of ERß1 gene. This study provides new insights in the distribution of ERs in immune cells. Furthermore, expression patterns of several immune response genes differ significantly between phases of the menstrual cycle, supporting a role for sex hormones in the immune response.
Assuntos
Imunidade/genética , Leucócitos Mononucleares/metabolismo , Ciclo Menstrual/genética , Receptores de Estrogênio/genética , Adulto , Idoso , Estudos de Coortes , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Ciclo Menstrual/metabolismo , Ciclo Menstrual/fisiologia , Pessoa de Meia-Idade , Pós-Menopausa/genética , Pós-Menopausa/metabolismo , Pré-Menopausa/genética , Pré-Menopausa/metabolismo , Receptores de Estrogênio/metabolismo , Fatores de TempoRESUMO
PURPOSE: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. EXPERIMENTAL DESIGN: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors. RESULTS: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). CONCLUSIONS: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF.See related commentary by Hunter et al., p. 5543.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor ErbB-2/genética , Tamoxifeno/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Gosserrelina/administração & dosagem , Gosserrelina/efeitos adversos , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Pré-Menopausa/efeitos dos fármacos , Pré-Menopausa/genética , Intervalo Livre de Progressão , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Tamoxifeno/efeitos adversosRESUMO
OBJECTIVE: The alternations of mtDNA may play an important role in the molecular pathogenesis and process of Pelvic Organ Prolapse (POP) formation in both pre-menopausal and post-menopausal women. The aim of the present study is to analyze the association between the mitochondrial biogenesis gene and development of POP in the uterosacral ligaments (UL) of pre-menopausal women. MATERIALS AND METHODS: Seventy one pre-menopausal women, all below 52 years of age, were enrolled in this study. UL biopsies were obtained from uterine specimens taken from 33 women with POP (n = 33, study group) and 38 myoma patients without POP (n = 38, control group). Quantitative Real-Time PCR was performed to measure mitochondrial DNA (mtDNA) copy number and mtDNA4977. Western blotting and immunohistochemistry were used to assess the protein expression of PGC-1α, TFAM, NRF-1 and NRF-2. Statistical analysis was performed using SPSS statistical software and the Mann-Whitney U test, and the continuous variables were analyzed using the Student's t-test in demographic data. RESULTS: There were no significant differences in the patient demographics between the two groups (p > 0.05). The mtDNA copy number in the UL of pre-menopausal patients with prolapse was significantly higher than that in the no prolapse group (p = 0.008). There were no significant differences between the mtDNA4977 of the POP and non-POP groups, but a significantly higher expression of PGC-1α in the POP group compared to the non-POP group (1.59 ± 1.30 v.s. 0.66 ± 0.53; p = 0.036). The expression of TFAM in the POP group was higher than in the non-POP group). There was no significant difference in the TFAM(p = 0.377), NRF-1 and NRF-2 expression between the POP and non-POP groups (p = 0.647; p = 0.682). CONCLUSIONS: Changes in the PGC-1α and mtDNA copy number may play a role in the development of Pelvic Organ Prolapse in pre-menopausal patients.
Assuntos
Variações do Número de Cópias de DNA , Regulação da Expressão Gênica , Prolapso de Órgão Pélvico/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Pré-Menopausa/genética , Estudos de Coortes , DNA Mitocondrial/análise , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Prolapso de Órgão Pélvico/epidemiologia , Prolapso de Órgão Pélvico/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
Estrogen regulates bone homeostasis and has a cardio-protective effect. Its physiological functions are mediated through receptors (ER) whose expression can be regulated by presence or absence of polymorphisms. However, the association between ER polymorphisms and BMD as well as lipids are inconsistent. The aim of the study was to investigate whether polymorphisms in ESR are associated with bone mineral density (BMD) and lipids in a cohort of Indian women. We studied PvuII, XbaI polymorphisms in ESR1 and AluI, RsaI polymorphisms in ESR2 genes and their association with bone mineral density (BMD) and lipids in premenopausal (nâ¯=â¯293, mean age: 33.01⯱â¯5.23â¯years) and postmenopausal (nâ¯=â¯145, mean age: 56.91⯱â¯7.1â¯years) women from Northeast India. AluI and RsaI polymorphisms in ESR2 gene were associated with BMD in postmenopausal women. Logistic regression analysis adjusted for age, BMI, tobacco and alcohol consumption revealed that xx genotype in XbaI polymorphism is associated with osteopenia at spine (ORâ¯=â¯3.3, 95% CIâ¯=â¯1.067-10.204) in postmenopausal women suggesting that allele X is protective (ORâ¯=â¯0.419, 95% CIâ¯=â¯0.177-0.991). Genotype aa in AluI polymorphism, seemed to be protective (ORâ¯=â¯0.092 for osteopenia; ORâ¯=â¯0.152 for osteoporosis) at spine whereas A allele was associated with osteopenia at femur (ORâ¯=â¯2.123, 95% CIâ¯=â¯1.079-4.166) in postmenopausal women. Allele r of RsaI polymorphism, was associated with osteoporosis at spine (ORâ¯=â¯3.222, 95% CIâ¯=â¯1.302-7.96). Thus, AIuI polymorphism of ESR2 gene was associated with spinal and femoral BMD whereas RsaI only with spinal BMD in postmenopausal women and ESR genotypes were not associated with lipids.
Assuntos
Doenças Ósseas Metabólicas/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Lipídeos/análise , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/genética , Pré-Menopausa/genética , Absorciometria de Fóton , Adulto , Densidade Óssea , Doenças Ósseas Metabólicas/metabolismo , Feminino , Fêmur/diagnóstico por imagem , Estudos de Associação Genética , Humanos , Índia , Modelos Logísticos , Pessoa de Meia-Idade , Coluna Vertebral/diagnóstico por imagem , População Branca/genéticaRESUMO
The adipokine lipocalin 2 (LCN2) is linked to insulin resistance. Its expression in human adipose tissue (AT) can be regulated in a sex-specific manner by a synthetic glucocorticoid, dexamethasone, suggesting an underlying role of sex steroids. We show that 17-ß-estradiol (E2) dose-dependently increased LCN2 gene expression in subcutaneous AT from postmenopausal women. This was also seen in the presence of estrogen receptor (ER) α antagonist alone but not with ERß antagonist, suggesting that E2 effects on LCN2 are mediated via ERß pathway. Dexamethasone alone or E2+dexamethasone had no significant effect on LCN2. However, E2+dexamethasone increased LCN2 expression with ERα-blockade. Dexamethasone reduced ERα but increased ERß expression. Dexamethasone can regulate LCN2 expression via inhibition of ERα and stimulation of ERß and may contribute to the development of glucocorticoid-induced insulin resistance in human AT. In conclusion, ERß and ERα pathways have opposite effects on LCN2 expression and they interact with glucocorticoid action.
Assuntos
Tecido Adiposo/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Resistência à Insulina , Lipocalina-2/genética , Adulto , Idoso , Dexametasona/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipocalina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Pós-Menopausa/genética , Pré-Menopausa/genéticaRESUMO
PURPOSE: The role of non-genetic factors as modifiers of TP53-related hereditary breast cancer (BC) risk is debated. In this regard, little is known about the impact of germline TP53 mutations on BC in sub-Saharan Africa, where the disease often presents in non-contraceptive multiparous premenopausal women with extended history of breastfeeding. Herein, we report the germline TP53 mutations found in a series of 92 Sudanese premenopausal BC patients characterized for reproductive history. METHODS: The entire TP53 coding sequence, including intron-exon boundaries and UTRs, was analyzed via DHPLC and direct sequencing, and the association of TP53 genotypes with BC risk and with individual lifetime exposures to reproductive factors was investigated with statistical tools. RESULTS: The germline TP53 mutation spectrum comprised 20 variants, 15 in the non-coding and 5 in the coding region. The latter included a deleterious missense mutation, c.817C>T (p.Arg273Cys), in a unique patient, and the common and functionally relevant coding polymorphism at amino acid 72 [Pro72Arg (rs1042522)]. The non-coding mutations included c.919+1G>A, a known deleterious splice site mutation, also in a unique patient. Notably, the 2 carriers of deleterious TP53 mutations clustered in the subset of cases with stronger reproductive history relative to childbearing age. When analyzed in comparison to population controls, the codon 72 polymorphism did not reveal associations with BC. CONCLUSIONS: Our study suggests that the codon 72 Arg>Pro polymorphism is not implicated in premenopausal BC susceptibility, whereas multiparity and breastfeeding might be BC risk factors for carriers of deleterious TP53 mutations.
Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Reprodução/genética , Proteína Supressora de Tumor p53/genética , Adulto , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/fisiopatologia , Feminino , Testes Genéticos , Genótipo , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Paridade/genética , Gravidez , Pré-Menopausa/genética , Pré-Menopausa/fisiologia , Reprodução/fisiologia , História Reprodutiva , Sudão/epidemiologiaRESUMO
BACKGROUND: In Latin America (LA), there is a high incidence rate of breast cancer (BC) in premenopausal women, and the genomic features of these BC remain unknown. Here, we aim to characterize the molecular features of BC in young LA women within the framework of the PRECAMA study, a multicenter population-based case-control study of BC in premenopausal women. METHODS: Pathological tumor tissues were collected from incident cases from four LA countries. Immunohistochemistry (IHC) was performed centrally for ER, PR, HER2, Ki67, EGFR, CK5/6, and p53 protein markers. Targeted deep sequencing was done on genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissues and their paired blood samples to screen for somatic mutations in eight genes frequently mutated in BC. A subset of samples was analyzed by exome sequencing to identify somatic mutational signatures. RESULTS: The majority of cases were positive for ER or PR (168/233; 72%), and 21% were triple-negative (TN), mainly of basal type. Most tumors were positive for Ki67 (189/233; 81%). In 126 sequenced cases, TP53 and PIK3CA were the most frequently mutated genes (32.5% and 21.4%, respectively), followed by AKT1 (9.5%). TP53 mutations were more frequent in HER2-enriched and TN IHC subtypes, whereas PIK3CA/AKT1 mutations were more frequent in ER-positive tumors, as expected. Interestingly, a higher proportion of G:C>T:A mutations was observed in TP53 in PRECAMA cases compared with TCGA and METABRIC BC series (27% vs 14%). Exome-wide mutational patterns in 10 TN cases revealed alterations in signal transduction pathways and major contributions of mutational signatures caused by altered DNA repair pathways. CONCLUSIONS: These pilot results on PRECAMA tumors give a preview of the molecular features of premenopausal BC in LA. Although the overall mutation burden was as expected from data in other populations, mutational patterns observed in TP53 and exome-wide suggested possible differences in mutagenic processes giving rise to these tumors compared with other populations. Further -omics analyses of a larger number of cases in the near future will enable the investigation of relationships between these molecular features and risk factors.
Assuntos
Neoplasias da Mama/genética , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Genes p53 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Incidência , América Latina/epidemiologia , Pessoa de Meia-Idade , Mutação , Projetos Piloto , Pré-Menopausa/genética , Pré-Menopausa/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento do Exoma , Adulto JovemRESUMO
AIM: We investigated the interaction of CYP2C19 and CYP2D6 genotype on clinical outcome in tamoxifen-treated breast cancer patients. MATERIALS & METHODS: A cohort of 306 patients on tamoxifen treatment for a minimum of 1 year were employed to analyze the effect of genotype-predicted phenotype on relapse-free survival. RESULTS & CONCLUSION: We show that the group with worst outcome and highest risk of relapse is that of 2C19↑-2D6↓ (hazard ratio: 2.94), when adjusting for age, Nottingham prognostic index and adjuvant chemotherapy. Furthermore, the effect of 2C19↑-2D6↓genotype-predicted phenotype is greatly enhanced in premenopausal patients (hazard ratio: 21.08). We hypothesize that poor bioactivation of tamoxifen in patients with low CYP2D6 activity and high CYP2C19 metabolism represents a tamoxifen-treated patient group that has the worst clinical outcome.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Pré-Menopausa/genética , Resultado do TratamentoRESUMO
The underlying cause of stress urinary incontinence (SUI) is an anatomical abnormality associated with paraurethral connective tissue dysfunction. The question as to whether estrogens affect the quality of that tissue remains unexplained. Samples of paraurethral connective tissue from 81 women were examined (the SUI's n = 49; the control's n = 32). In both groups, the patients were subdivided into pre- and postmenopausals. Primary study outcome was comparison of the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERß) gene and protein in paraurethral tissue between SUI and control group. Secondary study outcome was comparison of these receptors according to hormonal status of the patients and their age. In both examined groups, we found both ER proteins. The ERα gene expression was detected in-19/32 (SUI) samples and in 24/31 (control), and ERß gene expression 31/32 and 30/31 samples, respectively. The SUI's had significantly lower ERa gene expression premenopausally than the control's. The analysis found considerably lower ERß and reduced ERα gene expression in postmenopausals, approaches the significance level. There was also significant decrease in both receptors' genes expression in post-53 women, compared to younger patients. Spearman's correlation test revealed a statistically significant decrease in ERß gene with age. Both estrogen receptors are found in women's paraurethral tissue, so this tissue is an estrogen target. No correlation between ERß gene expression and immunoexpression and SUI was found. The ERα gene seems to play a key role in SUI in the premenopausal period, but ERß gene expression in the paraurethral connective tissue decreases with age.
Assuntos
Tecido Conjuntivo/metabolismo , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Incontinência Urinária por Estresse/genética , Adulto , Idoso , Envelhecimento/genética , Envelhecimento/fisiologia , Estradiol/sangue , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Hormônio Foliculoestimulante/sangue , Expressão Gênica , Humanos , Hormônio Luteinizante/sangue , Pessoa de Meia-Idade , Pós-Menopausa/genética , Pré-Menopausa/genética , UretraRESUMO
Objective The aim of this study was to determine whether a novel polymorphism ( Tru9I) in the low penetrance vitamin D receptor (VDR) gene is associated with risk of premenopausal breast cancer (BC). Methods This case-control study included 228 patients with BC and 503 healthy women living in Pakistan who were analyzed for the VDR Tru9I (rs757343) single nucleotide polymorphism. BC cases were histopathologically confirmed, and all healthy controls were age-matched with patients (age range, 20-45 years). DNA was extracted, and the polymerase chain reaction and restriction fragment length polymorphism assays were performed. Results The VDR Tru9I polymorphism was not significantly associated with premenopausal BC. However, the risk of BC was associated with the 'uu' genotype (odds ratio [OR], 1.141; 95% confidence interval [95% CI], 0.206-6.317). Further, mutant Tru9I was significantly associated with Grade IV carcinoma (OR, 5.36; 95% CI, 1.181-24.338). Conclusion The VDR Tru9I 'uu' genotype may increase the risk of premenopausal BC.
Assuntos
Neoplasias da Mama/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Penetrância , Polimorfismo de Nucleotídeo Único/genética , Pré-Menopausa/genética , Receptores de Calcitriol/genética , Neoplasias da Mama/patologia , Feminino , Frequência do Gene , Humanos , Fatores de RiscoRESUMO
BACKGROUND: Progesterone and androgens are important for normal development and tumorigenesis of the breast. PATIENTS AND METHODS: Breast tissue samples from 49 premenopausal women were obtained. The progesterone receptors (PRA, PRB, PGRMC1 and PGRMC2) and the androgen receptor (AR) were determined in malignant and benign breast tumors and control tissues. RESULTS: The PRB and AR mRNA levels were highest in tumors. PGRMC1 and PGRMC2 mRNA levels were higher in malignant tumors compared to their paired normal tissues. PRA protein showed most immunostaining in benign tumors. PRB immunostaining varied according to menstrual phase. AR immunostaining was highest in the glands of malignant tumors. CONCLUSION: Progesterone and androgen receptors are differently regulated in tumors compared to normal breast tissues. A malignant breast tumor could appear PR-negative if collected in the luteal phase, but positive in the follicular phase. This finding may have clinical implications.
Assuntos
Regulação Neoplásica da Expressão Gênica , Pré-Menopausa/genética , Receptores Androgênicos/genética , Receptores de Progesterona/genética , Adulto , Feminino , Fase Folicular/genética , Fase Folicular/metabolismo , Humanos , Imuno-Histoquímica , Fase Luteal/genética , Fase Luteal/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Pré-Menopausa/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Progesterona/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study (SMWHS) experienced one of the three symptom severity clusters identified through latent class analysis: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); low-severity hot flashes with moderate levels of all other symptom groups (moderate severity); and low levels of all symptom groups (low severity). In an effort to determine whether gene polymorphisms were associated with these symptom severity classes, we tested associations between gene polymorphisms in the estrogen synthesis pathways (cytochrome P450 19 [CYP 19] and 17 beta hydroxysteroid dehydrogenase [ 17HSDB1]) and the three symptom severity clusters. SMWHS participants ( N = 137) recorded symptoms monthly in diaries and provided buccal smears for genotyping. Multilevel latent class analysis with multinomial regression was used to determine associations between gene polymorphisms and symptom severity clusters. Only the 17HSDB1 polymorphisms ( rs615942 and rs592389) were associated significantly with the high-severity hot flash cluster versus the low-severity symptom cluster. None of the polymorphisms was associated with the moderate-severity cluster versus the low-severity symptom cluster. Findings of associations of the 17HSDB1 polymorphisms with the high-severity hot flash symptom cluster are consistent with those of an association between 17HSDB1 polymorphisms and hot flashes in the Study of Women and Health Across the Nation population and our previous findings of associations between these polymorphisms with greater estrone levels.
Assuntos
Estrogênios/biossíntese , Estrogênios/genética , Pós-Menopausa/genética , Pós-Menopausa/fisiologia , Pré-Menopausa/genética , Pré-Menopausa/fisiologia , Síndrome , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Polimorfismo GenéticoRESUMO
Outcomes based on menopausal status of breast cancer (BC) patients who are BRCA mutations carriers (BRCAm) are not well known. A prospective database identified 88 BRCAm with BC from 2005 to 2015. Of the 88 patients, 68 (77.3%) women were premenopausal (Pre-M) and 20 (22.7%) were postmenopausal (Post-M). In the Pre-M group, 52.9 per cent of patients had triple-negative (TN) BC, whereas in the Post-M group, there were more estrogen receptor +(65%; P = 0.129) and less TN (25%; P = 0.041) tumors. Median tumor size was significantly larger in the Pre-M group compared with the Post-M group (P <0.001). Pre-M women were more likely to present with stage III cancers (14.7% vs 0%, respectively, P = 0.082). Ten-year overall survival was 87.9 per cent in the Pre-M group and 93.8 per cent in the Post-M group (P = 0.44), and 25.3 per cent of Pre-M women had recurrences compared with 11.5 per cent of Post-M women (P = 0.24). Premenopausal BRCAm with BC are more likely to have TN, higher stage disease, and twice the number of recurrences at 10 years than Post-M BRCAm. Our study is the first to show worse BC outcomes for Pre-M BRCAm compared with Post-M BRCAm women.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Mutação/genética , Adulto , Idoso , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Pós-Menopausa/genética , Pré-Menopausa/genética , Estudos Prospectivos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidadeRESUMO
Human endometrium undergoes extensive regeneration on a cyclic basis in premenopausal women and likely occurs through the contribution of stem/progenitor cells. Menopause results in the permanent cessation of menstrual cycles and is preceded by perimenopause, a period of several years in which endocrine and biological changes occur and is a period of risk for endometrial proliferative disorders. The objectives of this study were to identify endometrial mesenchymal stem cells (eMSC) and endometrial stromal fibroblasts (eSF) in endometrium of perimenopausal women and perform expression profile analysis of perimenopausal eMSC and eSF to gain insight into the biology of stem/progenitor and lineage cell populations during the transition to menopause. Endometrial tissue was collected from perimenopausal and premenopausal women (n = 9 each). Microarray analysis was performed on fluorescence-activated cell sorting-isolated eSF and eMSC, and data were validated by quantitative real-time PCR. Principal component analysis showed that cells clustered into three distinct groups in 3-dimensional space: perimenopausal eMSC and premenopausal eMSC clustered together, while perimenopausal eSF and premenopausal eSF formed two discrete clusters separate from eMSC. Hierarchical clustering revealed a branching pattern consistent with principle clustering analysis results, indicating that eMSC from premenopausal and perimenopausal women exhibit similar transcriptomic signatures. Pathway analysis revealed dysregulation of cytoskeleton, proliferation, and survival pathways in perimenopausal vs. premenopausal eSF. These data demonstrate that cell populations have altered gene expression in perimenopausal vs. premenopausal endometrium, and that perimenopausal eSF had altered pathway activation when compared to premenopausal eSF. This study provides insight into aging endometrium with relevance to function in reproductively older women.
Assuntos
Endométrio/citologia , Endométrio/fisiologia , Fibroblastos/fisiologia , Células-Tronco Mesenquimais/fisiologia , Perimenopausa/genética , Perimenopausa/fisiologia , Pré-Menopausa/genética , Pré-Menopausa/fisiologia , Transcriptoma/genética , Adulto , Linhagem da Célula , Análise por Conglomerados , DNA/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Análise em Microsséries , Pessoa de Meia-Idade , Análise de Componente Principal , RNA/genética , Adulto JovemRESUMO
Stromal factors have been identified as important for tumorigenesis and metastases of breast cancer. From 49 premenopausal women, samples were collected from benign or malignant tumors and the seemingly normal tissue adjacent to the tumor. The factors studied, with real-time polymerase chain reaction (PCR) and immunohistochemistry, were cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), syndecan-1 (S-1) and connective tissue growth factor (CTGF). COX-1 and S-1 mRNA levels were higher in the malignant tumors than in normal and benign tissues. The COX-2 mRNA level was lower in the malignant tumor than in the normal tissue, while CTGF mRNA did not differ between the groups. COX-1 immunostaining was higher in stroma from malignant tumors than in benign tissues, whereas COX-2 immunostaining was higher in the malignant tissue. Glandular S-1 immunostaining was lower in malignant tumors compared to benign and normal tissues, and the opposite was found in stroma. Conclusively, mRNA levels of COX-1 and COX-2 were oppositely regulated, with COX-1 being increased in the malignant tumor while COX-2 was decreased. S-1 protein localization switched from glandular to stromal cells in malignant tissues. Thus, these markers are, in premenopausal women, localized and regulated differently in normal/benign breast tissue as compared to the malignant tumor.
Assuntos
Neoplasias da Mama/genética , Mama/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Sindecana-1/genética , Adulto , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pré-Menopausa/genética , Pré-Menopausa/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Sindecana-1/metabolismo , Adulto JovemRESUMO
BACKGROUND: Endogenous sex hormones are well-established risk factors for breast cancer; the contribution of specific oestrogen metabolites (EMs) and/or ratios of specific EMs is less clear. We have previously identified a CYP3A7*1C allele that is associated with lower urinary oestrone (E1) levels in premenopausal women. The purpose of this analysis was to determine whether this allele was associated with specific pathway EMs. METHODS: We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS. RESULTS: In addition to having lower urinary E1 levels, CYP3A7*1C carriers had significantly lower levels of four of the 2-hydroxylation pathway EMs that we measured (2-hydroxyestrone, P=1.1 × 10-12; 2-hydroxyestradiol, P=2.7 × 10-7; 2-methoxyestrone, P=1.9 × 10-12; and 2-methoxyestradiol, P=0.0009). By contrast, 16α-hydroxylation pathway EMs were slightly higher in carriers and significantly so for 17-epiestriol (P=0.002). CONCLUSIONS: The CYP3A7*1C allele is associated with a lower urinary E1 levels, a more pronounced reduction in 2-hydroxylation pathway EMs and a lower ratio of 2-hydroxylation:16α-hydroxylation EMs in premenopausal women. To further characterise the association between parent oestrogens, EMs and subsequent risk of breast cancer, characterisation of additional genetic variants that influence oestrogen metabolism and large prospective studies of a broad spectrum of EMs will be required.
Assuntos
Citocromo P-450 CYP3A/genética , Estrogênios/metabolismo , Pré-Menopausa , Adolescente , Adulto , Alelos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/urina , Regulação para Baixo/genética , Estrona/urina , Feminino , Triagem de Portadores Genéticos , Humanos , Hidroxilação , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Pré-Menopausa/genética , Pré-Menopausa/urina , Fatores de Risco , Adulto JovemRESUMO
X-ray repair cross complementary group gene is one of the most studied candidate gene involved in different types of cancers. Studies have shown that X-ray repair cross complementary genes are significantly associated with increased risk of breast cancer in females. Moreover, studies have revealed that X-ray repair cross complementary gene polymorphism significantly varies between and within different ethnic groups globally. The present case-control study was aimed to investigate the association of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer in females from northeastern region of India. The present case-control study includes histopathologically confirmed and newly diagnosed 464 cases with breast cancer and 534 apparently healthy neighborhood community controls. Information on sociodemographic factors and putative risk factors were collected from each study participant by conducting face-to-face interviews. Genotyping of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) was carried out by polymerase chain reaction-restriction fragment length polymorphism. For statistical analysis, both univariate and multivariate logistic regression analyses were performed. We also performed stratified analysis to find out the association of X-ray repair cross complementary genes with the risk of breast cancer stratified based on menstrual status. This study revealed that tryptophan allele (R/W-W/W genotype) in X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer (adjusted odds ratio = 1.44, 95% confidence interval = 1.06-1.97, P < .05 for R/W-W/W genotype). Moreover, it was found that tryptophan allele (W/W genotype) at codon 194 of X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer in premenopausal females (crude odds ratio = 1.66, 95% confidence interval = 1.11-2.46, P < .05 for R/W-W/W genotype). The present study did not reveal any significant association of X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer. The present study has explored that X-ray repair cross complementary 1A (Arg194Trp) gene polymorphism is significantly associated with the increased risk of breast cancer in premenopausal females from northeastern region of India which may be beneficial for prognostic purposes.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adulto , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Reparo do DNA/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pré-Menopausa/genética , Fatores de RiscoRESUMO
Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo- or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre- and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the pre-menopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.
Assuntos
Neoplasias da Mama/genética , Dosagem de Genes , Fator de Crescimento de Hepatócito/genética , Recidiva Local de Neoplasia/genética , Proteínas Proto-Oncogênicas c-met/genética , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Feminino , Amplificação de Genes , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Imuno-Histoquímica , Mastectomia , Pessoa de Meia-Idade , Fosforilação , Pós-Menopausa/genética , Pré-Menopausa/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Radioterapia Adjuvante , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A genome-wide association study was performed on 1130 premenopausal women to detect common variants associated with three serum iron-related phenotypes. Total iron binding capacity was strongly associated (p=10(-14)) with variants in and near the TF gene (transferrin), the serum iron transporting protein, and with variants in HFE (p=4×10(-7)), which encodes the human hemochromatosis gene. Association was also detected between percent iron saturation (p=10(-8)) and variants in the chromosome 6 region containing both HFE and SLC17A2, which encodes a phosphate transport protein. No significant associations were detected with serum iron, but variants in HFE were suggestive (p=10(-6)). Our results corroborate prior studies in older subjects and demonstrate that the association of these genetic variants with iron phenotypes can be detected in premenopausal women.