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Background: The luminal subtype accounts for ~70% of newly diagnosed breast cancer patients. Although it has a better prognosis, approximately 30% of them develop a late relapse. Identifying those patients is of interest to improve treatment decisions. Methods: A retrospective observational, single-centre study based on data from medical records of 572 non-metastatic (I-III) invasive ductal breast carcinoma patients, 448 with luminal tumours and 124 with triple-negative tumours. Kaplan-Meier, Cox regression and time-dependent Cox regression were carried out to obtain the prognosis value of risk factors. Results: During a median observation of 5.5 years, 105 distant metastasis events and 105 all-cause deaths were observed. In addition to known clinicopathological factors (i.e., age, tumour size and lymph node metastasis), the high semi-quantitative expression of both hormone receptors was associated with distant metastasis-free survival (DMFS) (adjusted hazard ratio (HaR): 0.524 (0.316-0.867), p = 0.012) and overall survival (OS) (adjusted HaR: 0.486 (0.286-0.827), p = 0.008). The stratified analysis made it possible to identify risk modification factors. Subsequent stratification by histological grade, Ki-67 and semi-quantitative PR expression or, mainly, the composite semi-quantitative expression of hormone receptors (cHR) enabled the identification of luminal breast cancer patients of adjuvant schema at higher risk for metastasis and death. However, initial analyses including patients of neoadjuvant therapy pointed to a path of subsequent stratification by cHR and histological grade, also enabling grouping of luminal breast cancer patients with similar prognosis for DMFS (cHR ≤ 4+ G2 or G3 versus triple-negative, adjusted HaR: 0.703 (0.415-1.189), p = 0.189) and OS (cHR ≤4+ G2 or G3 versus triple-negative, adjusted HaR: 0.662 (0.403-1.088), p = 0.104). Conclusion: The semi-quantitative expression of both cHR, Ki-67 proliferation index and histological grade can identify luminal breast cancer patients at greater risk of developing metastasis and death when combined in a hierarchical fashion, and could be useful for a better prognosis stratification in services from low- and middle-income countries.
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OBJECTIVE: To evaluate if genetic polymorphisms in the oestrogen receptor 1 (ESR1) and oestrogen receptor 2 (ESR2) genes encoded for oestrogen receptors alpha (ERα) and beta (ERß) are involved in permanent tooth size. DESIGN: Cross-sectional study. SETTING: Orthodontic Clinic at School of Dentistry of Ribeirão Preto, University of São Paulo. PARTICIPANTS: A total of 108 orthodontic patients. MATERIALS AND METHODS: Pre-treatment orthodontic records were evaluated. Dental casts were used to determine the maximum crown measurements of fully erupted permanent teeth in the mesiodistal dimensions. Second and third molars were not included in the analysis. Genomic DNA samples were used for the genotyping of four genetic polymorphisms: ESR1 (rs9340799 and rs2234693) and ESR2 (rs1256049 and rs4986938). The associations between tooth size and sex were evaluated using t test. The associations between tooth size and genotype were analysed with linear regression and adjusted by sex at an alpha of P⩽0.05. RESULTS: Female patients presented smaller tooth size than male patients. A statistically significant difference was observed in almost all teeth (P<0.05). The genetic polymorphisms in rs9340799, rs2234693, rs1256049 and rs4986938 were associated with some tooth sizes in both the maxilla and mandible (P<0.05). CONCLUSION: This study provides evidence that genetic polymorphisms in ESR1 and ESR2 could be associated with tooth size in permanent teeth.
Assuntos
Polimorfismo de Nucleotídeo Único , Receptores de Estrogênio , Estudos Transversais , Receptor alfa de Estrogênio , Receptor beta de Estrogênio/genética , Feminino , Humanos , Masculino , Mandíbula , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
OBJECTIVE: The role of oestrogen in craniofacial growth still remains unclear. Therefore, the present study aimed to assess the effect of oestrogen deficiency on maxilla and mandible dimensions. SETTING AND SAMPLE POPULATION: The study was conducted at the Department of Pediatric Dentistry at the School of Dentistry of Ribeirão Preto, University of São Paulo, and used forty female Wistar rats. MATERIAL AND METHODS: Ovariectomy (OVX) and placebo surgery (Sham) were performed when animals were twenty-one days old (prepubertal stage). Dimensions of the maxilla and mandible were assessed by craniometric analysis using radiographs, during and after puberty of the animals (45 and 63 days old, respectively). Quantitative real-time PCR and immunohistochemical analyses were performed to determine the expression and localization, respectively, of oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERß) in different growth sites of the evaluated structures at puberty. The differences between the groups for each outcome were evaluated using the t test with an established alpha error of 5%. RESULTS: There were significant differences between the OVX and Sham groups for horizontal and vertical linear measurements in the maxilla and the mandible at both pubertal and post-pubertal stages (P < .05). The ovariectomized rats showed significantly greater measures for all dimensions assessed. No differences in gene expression of ERα and ERß were identified at the different growth sites between the OVX and Sham groups (P > .05). Immunohistochemical analyses revealed the presence of both oestrogen receptors in osteoblasts and chondrocytes in the midpalatal suture and mandibular condyle, respectively, in the OVX and Sham groups. CONCLUSION: Our results suggest that oestrogen deficiency from the prepubertal stage might increase the growth of the maxilla and mandible in female rats.
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Maxila , Maturidade Sexual , Animais , Criança , Feminino , Humanos , Mandíbula , Ovariectomia , Ratos , Ratos WistarRESUMO
The molecular mechanisms underlying the ERα nuclear/cytoplasmic pool that modulates pituitary cell proliferation have been widely described, but it is still not clear how ERα is targeted to the plasma membrane. The aim of this study was to analyse ERα palmitoylation and the plasma membrane ERα (mERα) pool, and their participation in E2-triggered membrane-initiated signalling in normal and pituitary tumour cell growth. Cell cultures were prepared from anterior pituitaries of female Wistar rats and tumour GH3 cells, and treated with 10 nM of oestradiol (E2). The basal expression of ERα was higher in tumour GH3 than in normal pituitary cells. Full-length palmitoylated ERα was observed in normal and pituitary tumour cells, demonstrating that E2 stimulation increased both, ERα in plasma membrane and ERα and caveolin-1 interaction after short-term treatment. In addition, the Dhhc7 and Dhhc21 palmitoylases were negatively regulated after sustained stimulation of E2 for 3 h. Although the uptake of BrdU into the nucleus in normal pituitary cells was not modified by E2, a significant increase in the GH3 tumoural cell, as well as ERK1/2 activation, with this effect being mimicked by PPT, a selective antagonist of ERα. These proliferative effects were blocked by ICI 182780 and the global inhibitor of palmitoylation. These findings indicate that ERα palmitoylation modulated the mERα pool and consequently the ERK1/2 pathway, thereby contributing to pituitary tumour cell proliferation. These results suggest that the plasma membrane ERα pool might be related to the proliferative behaviour of prolactinoma and may be a marker of pituitary tumour growth.
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Membrana Celular/metabolismo , Proliferação de Células , Receptor alfa de Estrogênio/metabolismo , Neoplasias Hipofisárias/metabolismo , Animais , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Estrogênios/farmacologia , Feminino , Fulvestranto/farmacologia , Expressão Gênica/efeitos dos fármacos , Lipoilação/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Ratos WistarRESUMO
Prostate physiology is highly dependent on oestrogenic and androgenic homeostasis. Interferences in this equilibrium, especially in early periods of life, may disrupt the prostate and increase the susceptibility to the development of diseases with ageing. Taking this into account, and considering the increase of environmental chemicals with endocrine-disrupting potential such as bisphenol-A (BPA), this study aimed to evaluate the prostates of adult female gerbils exposed to BPA and BPA plus testosterone from pubertal to adult periods. Morphological, stereological and chemical analyses revealed that long-term BPA exposure, even in environmental dosages, increases the proliferative status of the prostate, increases the number of ERα-positive stromal cells and elicits the development of prostatic hyperplasia in adult female gerbils. Moreover, we also observed that the association with testosterone did not increase the proliferative status of the gland, which shows that low levels of BPA are enough to cause an oestrogenic disruption of the prostate in young adults. This evidence suggests that this oestrogenic endocrine disruptor may increase the susceptibility to prostatic disorders with ageing.