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1.
Zhonghua Yi Xue Za Zhi ; 101(44): 3625-3630, 2021 Nov 30.
Artigo em Chinês | MEDLINE | ID: mdl-34823278

RESUMO

Objective: To analyze the application, efficacy, and safety of palbociclib in hormone receptor positive (HR+) and HER2 negative (HER2-) advanced breast cancer in the real world. Methods: The information of patients who received palbociclib treatment from September 2018 to September 2020 was collected, and the general medical history data and disease characteristics were summarized. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and safety were analyzed. Results: A total of 55 patients with HR+/HER2-advanced breast cancer who received a treatment regimen containing palbociclib were enrolled. The ORR was 48.8%, and DCR was 88.4%. The median PFS was 12.0 months (95%CI, 11.1-13.0 months), and the median TTF was 8.50 months (95%CI, 2.5-14.5 months). Among them, palbociclib was superior to multi-line therapy in the first line (P=0.000 1). The prognosis of patients with non-liver metastases was better (P=0.01). Hematological toxicity was the focus of observation of adverse events, including leukopenia, neutropenia, and thrombocytopenia. The incidence rates of them were 78.2%, 85.5%, and 34.5%, respectively. No other grade 3-4 nonhematological toxicity was found. Conclusions: Palbociclib combined with endocrine therapy in patients with HR+/HER2-advanced breast cancer has good efficacy and controllable adverse reactions. It can be used as a first-line or multi-line treatment option for HR+/HER2-advanced breast cancer.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Hormônios/uso terapêutico , Humanos , Piperazinas , Piridinas , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona/uso terapêutico
2.
Clin Immunol ; 232: 108874, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34740841

RESUMO

Female sex hormones affect the immune response in the lower female genital tract. To understand their mechanisms of action, it is essential to define cell types expressing estrogen receptor (ER) and/or progesterone receptor (PR) in the human vaginal mucosa (VM). Here, we report that none of the dendritic cell (DC) subsets in the human VM expressed ERα or PR in situ. However, they were capable of expressing ERα, but not PR, after in vitro culture of the whole VM tissues. Similarly, ERα and/or PR expression by T cells in the VM tissues was also inducible rather than constitutive. In contrast, ERα and/or PR were constitutively expressed in HLA-DR- non-immune cell types (vimentin+, desmin+, or CD10+). These new findings will help us understand the mechanisms of action of female sex hormones in the modulation of immune response in the human VM and lower female genital tract.


Assuntos
Membrana Mucosa/metabolismo , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Vagina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Dendríticas/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Linfócitos T/metabolismo
3.
Rev Assoc Med Bras (1992) ; 67(7): 975-978, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34817509

RESUMO

OBJECTIVE: Gliomas are tumors originating from glial cells. Gliomas are the most common primary neoplasms of the central nervous system, with astrocytomas being the most prevalent glioma subtype. Progesterone regulates several reproductive processes, such as ovulation and sexual behavior, and influences neuronal excitability, learning, and the neoplastic proliferation of glial cells. Progesterone functions mainly by interacting with intracellular progesterone receptors to modify the expression of the genes involved in cell proliferation, angiogenesis, and epidermal growth factor production. As not many studies on the hormone receptors in glial tumors have been reported, the objective of this study was to evaluate the expression of these proteins in astrocytomas and to determine whether their expression levels vary according to the tumor grade. METHODS: This was a retrospective study using glial tumor paraffin blocks obtained from the São Marcos Hospital Pathology Department archives. Forty cases were divided equally into two groups, based on histological types and the World Health Organization criteria (low- and high-grade tumors). Progesterone receptor expression was analyzed by immunohistochemistry. The data were statistically analyzed using the Mann-Whitney U test and Spearman's correlation coefficient; results with p<0.05 were considered statistically significant. RESULTS: There were no statistically significant differences between the mean nuclear progesterone receptor expression of low-grade (0.1495) and high-grade (0.0937) astrocytomas (p=0.2). CONCLUSION: Progesterone receptors are present in both low- and high-grade gliomas; however, there is no significant difference in the levels of progesterone receptor expression between the tumor grades.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Feminino , Humanos , Progesterona , Receptores de Progesterona , Estudos Retrospectivos
4.
Lancet Oncol ; 22(11): 1573-1581, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34656225

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. METHODS: In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating. FINDINGS: Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68-0·88), with a median follow-up of 43·7 months (IQR 37·8-47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52-1·07), with a median follow-up of 39·4 months (IQR 37·0-42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9-not estimable) in the CDKI group and was 45·7 months (95% CI 41·7-not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67-0·89), with a median follow-up of 45·1 months (95% CI 39·2-48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs. INTERPRETATION: The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer. FUNDING: None.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fulvestranto/uso terapêutico , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Antagonistas do Receptor de Estrogênio/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Estados Unidos , United States Food and Drug Administration
5.
Rom J Morphol Embryol ; 62(1): 269-278, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34609431

RESUMO

The study aim was to evaluate the ultrasound (US) signs of the mammary lesions classified in the Breast Imaging-Reporting and Data System (BI-RADS) score category 3, 4, and 5, corresponding to US BI-RADS. It also followed the correlation between US changes of lesions suggestive for malignancy with the histopathological results and evaluated the proper management of those lesions. There were correlations of breast cancer (BC) subtypes with the receptors [estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2)], and Ki67 index, and the signs of conventional ultrasonography and US elastography. We selected 108 female patients examined with US, mammography and fine-needle biopsy who presented suspicions for malignancy lesions. Following the immunohistochemical analysis, they were classified in one of the BC subtypes. According to chi-squared analysis of molecular cancer subtypes correlation to receptors and Ki67 index, we found significant associations between both luminal A and luminal B HER2-negative subtypes and hormone receptors (ER, PR). These have an inverse relationship with Ki67 index elevated values; luminal B HER2-positive subtype has a direct association with HER2 presence; HER2-enriched subtype was statistically significant associated to HER2 presence and elevated Ki67 index values but had an inverse relationship to hormone receptors (ER, PR); triple-negative subtype was strongly associated to Ki67 index values and inversely correlated to ER and PR. We found luminal A subtype as being the most common and luminal B HER2-positive subtype as having the fewer cases.


Assuntos
Neoplasias da Mama , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Mamografia , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Ultrassonografia
6.
Elife ; 102021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34709177

RESUMO

Background: Decidualization of the uterine mucosa drives the maternal adaptation to invasion by the placenta. Appropriate depth of placental invasion is needed to support a healthy pregnancy; shallow invasion is associated with the development of severe preeclampsia (sPE). Maternal contribution to sPE through failed decidualization is an important determinant of placental phenotype. However, the molecular mechanism underlying the in vivo defect linking decidualization to sPE is unknown. Methods: Global RNA sequencing was applied to obtain the transcriptomic profile of endometrial biopsies collected from nonpregnant women who suffer sPE in a previous pregnancy and women who did not develop this condition. Samples were randomized in two cohorts, the training and the test set, to identify the fingerprinting encoding defective decidualization in sPE and its subsequent validation. Gene Ontology enrichment and an interaction network were performed to deepen in pathways impaired by genetic dysregulation in sPE. Finally, the main modulators of decidualization, estrogen receptor 1 (ESR1) and progesterone receptor B (PGR-B), were assessed at the level of gene expression and protein abundance. Results: Here, we discover the footprint encoding this decidualization defect comprising 120 genes-using global gene expression profiling in decidua from women who developed sPE in a previous pregnancy. This signature allowed us to effectively segregate samples into sPE and control groups. ESR1 and PGR were highly interconnected with the dynamic network of the defective decidualization fingerprint. ESR1 and PGR-B gene expression and protein abundance were remarkably disrupted in sPE. Conclusions: Thus, the transcriptomic signature of impaired decidualization implicates dysregulated hormonal signaling in the decidual endometria in women who developed sPE. These findings reveal a potential footprint that could be leveraged for a preconception or early prenatal screening of sPE risk, thus improving prevention and early treatments. Funding: This work has been supported by the grant PI19/01659 (MCIU/AEI/FEDER, UE) from the Spanish Carlos III Institute awarded to TGG. NCM was supported by the PhD program FDGENT/2019/008 from the Spanish Generalitat Valenciana. IMB was supported by the PhD program PRE2019-090770 and funding was provided by the grant RTI2018-094946-B-100 (MCIU/AEI/FEDER, UE) from the Spanish Ministry of Science and Innovation with CS as principal investigator. This research was funded partially by Igenomix S.L.


Assuntos
Decídua/patologia , Receptor alfa de Estrogênio/genética , Pré-Eclâmpsia/genética , Receptores de Progesterona/genética , Transdução de Sinais , Adulto , Decídua/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Pré-Eclâmpsia/metabolismo , Gravidez , Receptores de Progesterona/metabolismo , Adulto Jovem
7.
Life Sci ; 285: 120010, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34606849

RESUMO

AIMS: Hormone receptors are the main markers applied for prognosis of breast cancer subtypes. Among modulators, exogenous chemical agents known as endocrine disruptors interact with certain receptors, triggering molecular pathways or increasing their expression. Bisphenol A (BPA), a xenoestrogen, interacts with several hormone receptors. Thus, our aim was to characterize the hormone receptor status in the mammary gland (MG) of aged female Mongolian gerbils exposed to BPA in pregnancy and lactation. METHODS: We evaluated the expression of receptors for estrogens (ERα and ERß), progesterone (PR), prolactin (PRL-R), HER2/ErbB2, and androgen (AR) in normal and hyperplastic mammary tissue and in carcinomas developed after BPA exposure. KEY FINDINGS: BPA-exposed MG presented increased ERα, whereas ERß, PR, and PRL-R showed lower expression. AR and HER2/ErbB2 showed similar expression in normal and hyperplastic tissue from control, vehicle, and BPA groups. Both receptors were found in cytoplasm and nucleus in BPA-induced carcinoma. We demonstrate the presence of EZH2 expression, an epigenetic and epithelial-mesenchymal transition (EMT) marker, with a high H-score in BPA-exposed MG, which was associated with poor prognosis of cancer. Co-localization of ERα and EZH2 was present in normal and carcinoma features, corroborating the installation of ERα-positive mammary cancer associated with the EMT process. Enhanced EZH2 in BPA-exposed mammary tissue could decrease ERß expression and promote tumorigenesis progress through HER2/ErbB2. SIGNIFICANCE: The present study proposes the Mongolian gerbil as an experimental model for mammary carcinogenesis studies, based on BPA disruption that triggers a phenotype of increased ERα/HER2 positivity and depletion of ERß/PR expression.


Assuntos
Envelhecimento , Compostos Benzidrílicos/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Carcinogênese/induzido quimicamente , Disruptores Endócrinos/efeitos adversos , Glândulas Mamárias Animais/efeitos dos fármacos , Exposição Materna , Fenóis/efeitos adversos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Animais , Neoplasias da Mama/metabolismo , Carcinogênese/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Gerbillinae , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo
8.
Adv Exp Med Biol ; 1329: 443-474, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34664251

RESUMO

The tumor microenvironment (TME) is a complex infrastructure composed of stromal, epithelial, and immune cells embedded in a vasculature ECM. The microenvironment surrounding mammary epithelium plays a critical role during the development and differentiation of the mammary gland, enabling the coordination of the complex multihormones and growth factor signaling processes. Progesterone/progesterone receptor paracrine signaling interactions in the microenvironment play vital roles in stem/progenitor cell function during normal breast development. In breast cancer, the female sex hormones, estrogen and progesterone, and growth factor signals are altered in the TME. Progesterone signaling modulates not only breast tumors but also the breast TME, leading to the activation of a series of cross-communications that are implicated in the genesis of breast cancers. This chapter reviews the evidence that progesterone and PR signaling modulates not only breast epitheliums but also the breast TME. Furthermore, crosstalk between estrogen and progesterone signaling affecting different cell types within the TME is discussed. A better understanding of how PR and progesterone affect the TME of breast cancer may lead to novel drugs or a therapeutic approach for the treatment of breast cancer shortly.


Assuntos
Glândulas Mamárias Humanas , Receptores de Progesterona , Mama , Feminino , Humanos , Receptores de Progesterona/genética , Transdução de Sinais , Microambiente Tumoral
9.
J Int Med Res ; 49(10): 300060520967774, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34666529

RESUMO

OBJECTIVES: To investigate the relationship between high-molecular-weight cytokeratin (34ßE12) and clinicopathological parameters (including HER-2, Ki67 and steroid receptors) in breast cancer to determine its usefulness as a prognostic marker. METHODS: In this retrospective study, the expression level 34ßE12 was assessed in surgically resected breast cancer specimens by immunohistochemical staining. Data were correlated with the patients' clinicopathological parameters. RESULTS: Of the 348 breast cancer tissue samples, 232 (67%) showed positive expression of 34ßE12. There were statistically significant differences between the positive and negative 34ßE12 expression groups in tumour size, lymph node involvement, oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status. There were no differences between groups in age, tumour grade, or Ki67 status. In addition, patients who were positive for 34ßE12 had significantly extended overall survival. In multivariate analysis, the expression level of 34ßE12 was found to be a significant independent prognostic factor. CONCLUSION: These results suggest that positive 34ßE12 expression is associated with a favourable outcome in breast cancer and so may be a useful prognostic factor. Further studies are required to confirm these results.


Assuntos
Neoplasias da Mama , Queratinas , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Antígeno Ki-67/genética , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio , Receptores de Progesterona/genética , Estudos Retrospectivos
10.
Nat Commun ; 12(1): 5991, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645803

RESUMO

The reticulon-3 (RTN3)-driven targeting complex promotes clearance of misfolded prohormones from the endoplasmic reticulum (ER) for lysosomal destruction by ER-phagy. Because RTN3 resides in the cytosolic leaflet of the ER bilayer, the mechanism of selecting misfolded prohormones as ER-phagy cargo on the luminal side of the ER membrane remains unknown. Here we identify the ER transmembrane protein PGRMC1 as an RTN3-binding partner. Via its luminal domain, PGRMC1 captures misfolded prohormones, targeting them for RTN3-dependent ER-phagy. PGRMC1 selects cargos that are smaller than the large size of other reported ER-phagy substrates. Cargos for PGRMC1 include mutant proinsulins that block secretion of wildtype proinsulin through dominant-negative interactions within the ER, causing insulin-deficiency. Chemical perturbation of PGRMC1 partially restores WT insulin storage by preventing ER-phagic degradation of WT and mutant proinsulin. Thus, PGRMC1 acts as a size-selective cargo receptor during RTN3-dependent ER-phagy, and is a potential therapeutic target for diabetes.


Assuntos
Proteínas de Transporte/genética , Retículo Endoplasmático/metabolismo , Células Secretoras de Insulina/metabolismo , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Proinsulina/genética , Receptores de Progesterona/genética , Animais , Autofagia/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Retículo Endoplasmático/genética , Expressão Gênica , Células HEK293 , Humanos , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Lisossomos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Mutação , Proteínas do Tecido Nervoso/metabolismo , Cultura Primária de Células , Proinsulina/metabolismo , Ligação Proteica , Domínios Proteicos , Dobramento de Proteína , Proteólise , Ratos , Receptores de Progesterona/metabolismo
11.
J Int Med Res ; 49(10): 3000605211049977, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34713754

RESUMO

OBJECTIVE: We aimed to describe the differences in clinicopathological characteristics and overall survival (OS) between male and female breast cancer patients, and to develop a prognostic nomogram to predict survival in patients with male breast cancer (MBC). METHODS: Using the Surveillance, Epidemiology, and End Results database, we compared age, race, histological type, histological grade, tumor size, lymph node status, metastases, estrogen/progesterone receptor (ER/PR) and HER-2 status between male and female patients, and analyzed their relationships with OS. We established a nomogram and produced a calibration curve to observe its predictive effect. RESULTS: Age, race, T stage, N stage, bone and lung metastases, and histological type and grade differed between male and female patients. OS in male patients was related to age, tumor size, metastatic site, ER/PR status, and histological grade, but not to race or lymph node status. A nomogram was established, which showed good predictive performance for survival in MBC patients (area under the curve = 0.7). CONCLUSION: MBC has a worse prognosis than female breast cancer, mainly characterized by late onset age, late staging, high proportion of invasive non-specific histological types, high histological grade, and luminal breast cancer.


Assuntos
Neoplasias da Mama Masculina , Neoplasias da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/diagnóstico , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Nomogramas , Prognóstico , Receptores de Progesterona , Estudos Retrospectivos , Fatores de Risco
12.
BMC Musculoskelet Disord ; 22(1): 891, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670550

RESUMO

BACKGROUND: Rotator cuff (RC) tears represent a common cause of shoulder pain and dysfunction in adults. The disease affects primarily women and occurs mainly in the postmenopausal period. This study aimed to investigate immunohistochemically the presence of estrogen receptor-alpha (ER-⍺), estrogen receptor-beta (ER-ß) and progesterone receptor (PR) in the supraspinatus tendon of patients with RC tendinopathy, searching for gender differences of expression. A secondary aim was to evaluate potential links between their expression and the typical histopathological findings of the ailment. METHODS: Biopsies of the supraspinatus tendon were collected intraoperatively from 15 postmenopausal women and 9 men undergoing RC surgery. Specimens were stained with Haematoxylin/Eosin, Masson-Goldner Trichrome, Alcian Blu and immunohistochemical stainings for ER-⍺, ER-ß and PR were performed. Tendon alterations were evaluated with the Bonar histopathological scale. Statistical tests used in this study were the Spearman correlation coefficient and the Mann-Whitney U test. RESULTS: In the supraspinatus tendon, cells expressed ER-⍺ (p = 0.043), ER-ß (p = 0.048) and PR (p = 0.004) with statistically significant differences related to age and sex of patients. Immunoreactivity was seen in the nuclei of tenocytes and vascular cells. Postmenopausal women's samples showed a markedly higher expression of these receptors compared to their male counterpart. There was a positive correlation between the expression of ER-⍺ and ER-ß (r = 0.59; p = 0.02) and between ER-ß and PR (r = 0.72; p = 0.002) in women's samples. Furthermore, in postmenopausal women the PR expression decreased with age (r = - 0.56; p = 0.027). Only in women, the ER-ß expression positively correlated with the total Bonar histopathological score (p = 0.019) and the ER-ß vascular expression positively correlated with ground substance alterations (p = 0.029). CONCLUSIONS: These results reveal that ERs and PR are present in the supraspinatus tendon of patients with RC tears, suggesting a role of sex hormones in the pathogenesis of the disease.


Assuntos
Receptores de Estrogênio/metabolismo , Receptores de Progesterona , Lesões do Manguito Rotador/metabolismo , Estrogênios , Feminino , Humanos , Masculino , Estudos Retrospectivos
13.
PLoS One ; 16(9): e0255580, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34555047

RESUMO

PURPOSE: Decades of quality control efforts have raised the standards of immunohistochemistry (IHC), the principle method used for biomarker testing in breast cancer; however, computational pathology and reverse transcription quantitative PCR (RT-qPCR) may also hold promise for additional substantial improvements. METHODS: Herein, we investigated discrepancies in the assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and marker of proliferation Ki67 comparing routinely obtained IHC (and FISH) data (ORI) with the results of manual (REV) and semi-automated (DIA) re-evaluation of the original IHC slides and then with RNA expression data from the same tissue block using the MammaTyper® (MT) gene expression assay. RESULTS: Correlation for ER and PR was high between ORI IHC and the other three study methods (REV, DIA and RT-qPCR). For HER2, 10 out of 96 discrepant cases can be detected between ORI and REV that involved at least one call in the equivocal category (except for one case). For Ki67, 22 (29.1%) cases were categorized differently by either REV alone (n = 17), DIA alone (n = 15) or both (n = 10) and 28 cases (29.2%) for RT-qPCR. Most of the discrepant Ki67 cases changed from low to high between the original and following assessment and belonged to the intermediate Ki67 expression range (between 9 and 30%). CONCLUSIONS: Determination of the breast cancer biomarkers ER, PR, HER2 and Ki67 at the mRNA level shows high degree of correlation with IHC and compares well with correlations between original with subsequent independent manual or semi-automated IHC assessments. The use of methods with wider dynamic range and higher reproducibility such as RT-qPCR may offer more precise assessment of endocrine responsiveness, improve Ki67 standardization and help resolve HER2 cases that remain equivocal or ambiguous by IHC/FISH. In summary, our findings seem to configure RT-qPCR as a complementary method to be used in cases of either equivocal results or presenting, at the traditional determination assays, biomarkers expressions close to the cut-off values.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Testes Diagnósticos de Rotina/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Reprodutibilidade dos Testes
14.
Clin Obstet Gynecol ; 64(4): 813-836, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524172

RESUMO

Common benign gynecologic conditions such as uterine fibroids and endometriosis are linked to chronic pelvic pain, abnormal and heavy uterine bleeding, and infertility. Effective medical management of these diseases is an unmet need. The steroid hormones progesterone (P4), estrogen (E2), and testosterone play a major role in reproductive physiology and uterine pathologies. Notably, selective progesterone receptor modulators have shown considerable promise as treatment options for some hormone-dependent conditions. More limited data are available regarding the safety and efficacy of selective androgen receptor modulators. In this report we review current evidence for selective progesterone receptor modulators and selective androgen receptor modulators as treatment options for benign gynecologic conditions.


Assuntos
Doenças dos Genitais Femininos , Leiomioma , Neoplasias Uterinas , Feminino , Doenças dos Genitais Femininos/tratamento farmacológico , Humanos , Leiomioma/tratamento farmacológico , Progesterona , Receptores Androgênicos/genética , Receptores de Progesterona
15.
Int J Mol Sci ; 22(18)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34576245

RESUMO

Currently, infertility affects 8-12% of reproductive age couples worldwide, a problem that also affects women suffering from recurrent implantation failure (RIF). RIF is a complex condition resulting from many physiological and molecular mechanisms involving dynamic endometrium-blastocyst interaction. The most important are the endometrial receptivity process, decidualization, trophoblast invasion, and blastocyst nesting. Although the exact multifactorial pathogenesis of RIF remains unclear, many studies have suggested the association between hormone level imbalance, disturbances of angiogenic and immunomodulatory factors, certain genetic polymorphisms, and occurrence of RIF. These studies were performed in quite small groups. Additionally, the results are inconsistent between ethnicities. The present review briefly summarizes the importance of factors involved in RIF development that could also serve as diagnostic determinants. Moreover, our review could constitute part of a new platform for discovery of novel diagnostic and therapeutic solutions for RIF.


Assuntos
Implantação do Embrião/fisiologia , Endométrio/patologia , Infertilidade Feminina/genética , Adulto , Biomarcadores , Blastocisto , Endométrio/metabolismo , Estrogênios/metabolismo , Feminino , Glicodelina/metabolismo , Humanos , Sistema Imunitário , Fatores Imunológicos , Infertilidade Feminina/metabolismo , Fator Inibidor de Leucemia/metabolismo , Microbiota , Neovascularização Patológica , Progesterona/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Recidiva , Fatores de Risco , Vagina/microbiologia
16.
Gan To Kagaku Ryoho ; 48(9): 1127-1131, 2021 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-34521790

RESUMO

Occult breast cancer is rare in practice. We studied the clinical outcomes of 5 occult breast cancers, including 2 with Luminal and 3 with non-Luminal subtypes, for which the primary site was not detected in the breast-by-breast MRI. The percentage of occult breast cancers that we encountered at our hospital was 0.11%. The mean age was 54 years. The Ki-67 labeling index value was 30% or higher for all the patients except one. Four patients were administered neoadjuvant chemotherapy and all but one patient received non-mastectomy and axillary dissection plus radiotherapy. We observed recurrent cases in one example each of the Luminal and HER2 subtypes, and both patients were less than 40 years old. The estimates of the probability of 5 year recurrence-free survival and 5 year overall survival were 40.0% and 66.7%, respectively. One recurrence case was a patient negative for ER and positive for HER2 wherein a breast cancer lesion appeared in the breast during post-treatment follow-up. Intrabreast relapse, which is itself rare in occult breast cancer, was observed 4 years postoperatively after standard treatment. Although there was no deviation according to subtype rate, the Ki-67 labeling index value was high and the prognosis was poor in our 5 cases.


Assuntos
Neoplasias da Mama , Adulto , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Intervalo Livre de Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona
17.
Nat Commun ; 12(1): 5563, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548479

RESUMO

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Furanos/uso terapêutico , Cetonas/uso terapêutico , Adulto , Idoso , Apresentação do Antígeno/genética , Antígeno B7-H1/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Citocinas/sangue , Citocinas/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Estrogênios/metabolismo , Feminino , Perfilação da Expressão Gênica , Heterogeneidade Genética , Genoma Humano/genética , Genômica , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais/genética , Taxa de Sobrevida , Resultado do Tratamento
18.
Artigo em Inglês | MEDLINE | ID: mdl-34501783

RESUMO

Existing data on the expression of estrogen receptor (ERα) and progesterone receptor (PR) in fallopian tubes in postmenopausal women are mostly inconclusive. Therefore, we assessed ERα and PR immunoexpression in the oviducts of these women. One hundred postmenopausal women were divided into three groups based on time elapsed since the last menstrual period: (A) 1-5 years, (B) 6-10 years, and (C) ≥11 years. In all groups, both in the glandular epithelium and stroma of the ampulla and isthmus of the oviduct, immunolocalization of ERα and PR were noted. The glandular epithelium of the ampulla showed a higher percentage of PR-positive cells than the isthmus in each group. Regarding ERα, there were no significant differences. In the glandular epithelium in both the ampulla and isthmus, the percentage of ERα- and PR-positive cells was significantly higher than that in the stroma in each study group and higher in the A group than in the C group. In conclusion, in postmenopausal women, time elapsed since the last menstrual period in the fallopian tubes was positively correlated with the following: (1) the epithelium showed vacuolation of cytoplasm with greater frequency, (2) the proportion of ciliated cells decreased, and (3) the percentage of ERα- and PR-positive cells also decreased. The obtained results indicate a significant decrease in ERα and PR expression depending on the time that has elapsed since the last menstruation, which is undoubtedly related to the loss of the reproductive function of the patients.


Assuntos
Tubas Uterinas , Receptores de Progesterona , Animais , Receptor alfa de Estrogênio , Estrogênios , Feminino , Humanos , Pós-Menopausa , Progesterona , Receptores de Estrogênio
19.
J Transl Med ; 19(1): 398, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544424

RESUMO

BACKGROUND: The diversity and plasticity behind ER+/PR-/HER2- breast cancer have not been widely explored. It is essential to identify heterogeneous microenvironment phenotypes and investigate specific genomic events driving the formation of these phenotypes. METHODS: Based on the immune-related gene expression profiles of 411 ER+/PR-/HER2- breast cancers in the METABRIC cohort, we used consensus clustering to identify heterogeneous immune subtypes and assessed their reproducibility in an independent meta-cohort including 135 patients collected from GEO database. We further analyzed the differences of cellular and molecular characteristics, and potential immune escape mechanism among immune subtypes. In addition, we constructed a transcriptional trajectory to visualize the distribution of individual patient. RESULTS: Our analysis identified and validated five reproducible immune subtypes with distinct cellular and molecular characteristics, potential immune escape mechanisms, genomic drivers, as well as clinical outcomes. An immune-cold subtype, with the least amount of lymphocyte infiltration, had a poorer prognosis. By contrast, an immune-hot subtype, which demonstrated the highest infiltration of CD8+ T cells, DCs and NK cells, and elevated IFN-γ response, had a comparatively favorable prognosis. Other subtypes showed more diverse gene expression and immune infiltration patterns with distinct clinical outcomes. Finally, our analysis revealed a complex immune landscape consisting of both discrete cluster and continuous spectrum. CONCLUSION: Overall, this study revealed five heterogeneous immune subtypes among ER+/PR-/HER2- breast cancer, also provided important implications for clinical translations.


Assuntos
Neoplasias da Mama , Transcriptoma , Biomarcadores Tumorais , Neoplasias da Mama/genética , Feminino , Genômica , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio , Receptores de Progesterona , Reprodutibilidade dos Testes , Transcriptoma/genética , Microambiente Tumoral
20.
Breast Cancer Res Treat ; 189(3): 653-663, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34487293

RESUMO

PURPOSE: To determine prevalence, clinicopathological characteristics, initial treatments, and outcomes associated with low estrogen receptor (ER)-expressing invasive breast cancer. METHODS: This retrospective, non-interventional database study included patients undergoing surgery with curative intent for invasive ductal or lobular breast cancer. Patients were treated between January 2003-December 2012. Demographics, clinicopathological characteristics, initial treatments, and outcomes were abstracted from patient records. Patients were categorized using immunohistochemistry to determine ER, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) levels. ER-positive patients were subclassified as ER-low (1% to 10%) and ER-high (> 10%) according to the Allred Proportion Score. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared among groups by log-rank test. RESULTS: 5930 patients were included (median follow-up, 80.9 months). Of all patients included, 117 (2.0%) had ER-low tumors: 63 (53.8%) of whom had HER2- tumors and 54 (46.2%) HER2+ tumors. Five-year DFS and OS were highest in the ER-high/HER2- cohort (94.0% and 98.6%, respectively) and lowest in the triple-negative breast cancer (TNBC; 81.3% and 90.1%) and ER-low/HER2- (85.7% and 92.1%) cohorts. Menopausal status, elevated Ki-67, higher nuclear grade, higher tumor stage, presence of lymphovascular invasion, greater regional lymph node involvement, and larger tumor size were all potential prognostic factors for shorter DFS and OS. CONCLUSION: Patients with ER-low/HER2- breast cancer had similar clinicopathological characteristics, treatments, and outcomes as patients with TNBC irrespective of disease setting. Further research is needed to understand predictive and prognostic factors associated with ER-low/HER2- disease.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Feminino , Humanos , Prevalência , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , República da Coreia/epidemiologia , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia
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