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1.
BMC Cancer ; 22(1): 502, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35524219

RESUMO

BACKGROUND: The National Comprehensive Cancer Network recommends that patients with hormone receptor-positive early breast cancer be considered for adjuvant endocrine therapy (ET) after primary treatment like surgical excision. Adjuvant chemotherapy (CT) use primarily depends on risk of recurrence. Biomarkers such as Ki-67 potentially have most value in patients with intermediate risk factors, such as involvement of 1-3 positive nodes. This study evaluated the use of Ki-67 testing and treatment patterns in patients with HR+, human epidermal growth factor receptor 2-negative early breast cancer. METHODS: This was an observational retrospective cohort study of patients with electronic medical records from January 2010 to August 2018 treated for HR+, HER2- early breast cancer at Sarah Cannon sites in the United States (US). Overall, 567 patients were randomly selected after using the eligibility criteria: female or male ≥18 years, without distant metastases, and with available physician and pathology reports. Multivariable logistic regression was used to investigate factors predicting Ki-67 testing and test results. Descriptive analyses were applied to treatment patterns. RESULTS: Multivariable logistic regression analyses found no clinical or pathological factors that predicted whether Ki-67 testing had been ordered by physicians. Of all tested patients (N = 130), having Grade-2 tumors (OR, 7.95 [95% CI: 2.05, 30.9]; p = 0.0027) or Grade-3 tumors (OR, 95.3 [95% CI, 11.9, 760.7]; p < 0.001) at initial diagnosis was a predictor of high Ki-67 expression (≥20%). Ki-67 expression was tested in 23.6% (61/258) of patients with 1-3 positive nodes; 54.1% of them (33/61) had high Ki-67 expression (≥20%). While having a higher grade tumor predicted high Ki-67 (≥20%), 28.6% of patients with Grade-1 tumors also had high Ki-67 expression. Neo-adjuvant therapy was received by 16.0% of patients (91/567), most of whom (66/91; 72.5%) received CT alone. Adjuvant therapy, either endocrine and/or chemotherapy, was received by 92.6% (525/567) of patients and by 67.0% (61/91) of those who received neo-adjuvant therapy. Most (428/525, 81.5%) received ET in the adjuvant treatment setting. CONCLUSIONS: High grade tumors predicted high Ki-67 (≥20%) expression, but Ki-67 testing was not widely used in these US patients. Most HR+, HER2- early breast cancers were treated with adjuvant ET, with or without CT.


Assuntos
Neoplasias da Mama , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Humanos , Antígeno Ki-67/metabolismo , Masculino , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Estados Unidos
2.
Cell Death Dis ; 13(5): 447, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534460

RESUMO

Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Núcleo Celular/metabolismo , Humanos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
3.
JCO Glob Oncol ; 8: e2100359, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35436143

RESUMO

PURPOSE: Estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) are the mainstay of breast cancer management, and their prevalence rates vary among different populations possibly related to ethnic/genetic and/or socioeconomic status. In a previous study conducted at the King Hussein Cancer Center (published 2006), Jordan ER/PR/HER2 rates for patients diagnosed in 2003-2004 were 50.8%/57.5%/17.5%, respectively. The aim of this study is to revisit the prevalence rates to see if they have changed over the years with changing socioeconomic status. MATERIALS AND METHODS: We retrieved clinicopathologic data of all patients (1,185) diagnosed with breast cancer during 2018. The data included age, histologic type, grade, and ER/PR/HER2 status as determined by immunohistochemistry and/or fluorescence in situ hybridization for HER2. RESULTS: The mean age of patients was 52 (median = 51, range = 25-92) years, and the majority (73.2%) had invasive carcinoma of no special type. ER/PR/HER2 were 77.0%/72.4%./23.8%, respectively. Triple-negative breast cancers were 10.1%. In comparison with previous results of 2006, the changes are statistically significant. Similar changes were seen in other Middle Eastern populations. The current rates are close to those of Western populations. CONCLUSION: Rates of ER/PR/HER2 expression have significantly changed and are close to those of Western populations for ER/PR. We propose that such changes are secondary to the adoption of a westernized lifestyle and socioeconomic changes.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Jordânia/epidemiologia , Pessoa de Meia-Idade , Prevalência , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/metabolismo
4.
J Cancer Res Ther ; 18(1): 89-95, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35381768

RESUMO

Introduction: In this research, we studied how the expression of 14 stem genes (TERT; OCT3; SMO; MYC; SNAI2; MOB3B; KLF4; BMI1; VIM; FLT3; LAT; SMAD2; LMNB2; KLF1), as well as the TGF-ß1 cytokine gene and its TGFBR1 receptor in breast tumors before and after NAC is associated with clinical and morphological parameters and the disease outcome. Materials and Methods: The study included 82 patients with the morphologically verified diagnosis of T1-4N0-3M0 breast cancer (stages IIA - IIIB). The material was paired biopsy samples of tumor and surgical material for each patient. The stem genes expression was analyzed via qPCR. Results: As a result, we found that increased level of stem genes expression in breast tumors is associated with lymphogenic metastasis, young age, small tumor size, expression of estrogen and progesterone receptors, and the luminal B molecular subtype. NAC stimulates the expression of 7 out of 16 stem genes. Patients who further developed hematogenic metastases have twice as many hyperexpressed stem genes in their tumors before the treatment and after NAC than patients with no hematogenic metastases. The expression level of three genes - OCT3, LAT, and LMNB2 - in a residual tumor allows us to predict metastasis-free survival of patients with breast cancer of various molecular subtypes with a 79% accuracy. Conclusion: Thus, stem genes hyperexpression is associated with tumor progression.


Assuntos
Neoplasias da Mama , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estrogênios , Feminino , Expressão Gênica , Humanos , Neoplasia Residual , Prognóstico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
5.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35409203

RESUMO

Toxoplasma gondii (T. gondii), as an opportunistic pathogen, has special pathogenic effects on pregnant animals and humans. Progesterone (P4) is a critical hormone that supports pregnancy, and its levels fluctuate naturally during early pregnancy. However, little is known about the association of host P4 levels with the infectivity and pathogenicity of T. gondii. Our study showed that P4 significantly inhibited the invasion and proliferation of tachyzoites, resulting in abnormal cytoskeletal daughter budding and subsequent autophagy in vitro. To investigate the underlying mechanism, we identified a Toxoplasma gondii progesterone membrane receptor protein (TgPGRMC) that was localized to the mitochondrion and closely related to the effect of P4 on tachyzoites. The knockout of the pgrmc gene conferred resistance to P4 inhibitory effects. Our results prove the direct relationship between P4 single factors and T. gondii in vitro and demonstrate that TgPGRMC is an important link between T. gondii and P4, providing a new direction for research on T. gondii infection during pregnancy.


Assuntos
Toxoplasma , Toxoplasmose , Animais , Feminino , Gravidez , Progesterona/metabolismo , Progesterona/farmacologia , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Toxoplasma/metabolismo
6.
Cells ; 11(7)2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35406639

RESUMO

Progesterone has been shown to be a potent suppressor of several inflammatory pathways. During pregnancy, progesterone levels increase, allowing for normal pregnancy establishment and maintenance. The dysregulation of progesterone, as well as inflammation, leads to poor pregnancy outcomes. However, it is unclear how progesterone imbalance could impact inflammatory responses in the oviduct and subsequently result in early pregnancy loss. Therefore, in this review, we describe the role of progesterone signaling in regulating the inflammatory response, with a focus on the oviduct and pathological conditions in the Fallopian tubes.


Assuntos
Tubas Uterinas , Progesterona , Animais , Tubas Uterinas/metabolismo , Feminino , Humanos , Oviductos/metabolismo , Gravidez , Progesterona/metabolismo , Receptores de Progesterona/metabolismo
7.
Cells ; 11(7)2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35406659

RESUMO

Endometriosis is a significant disease characterized by infertility and pelvic pain in which endometrial stromal and glandular tissue grow in ectopic locations. Altered responsiveness to progesterone is a contributing factor to endometriosis pathophysiology, but the precise mechanisms are poorly understood. Progesterone resistance influences both the eutopic and ectopic (endometriotic lesion) endometrium. An inability of the eutopic endometrium to properly respond to progesterone is believed to contribute to the infertility associated with the disease, while an altered responsiveness of endometriotic lesion tissue may contribute to the survival of the ectopic tissue and associated symptoms. Women with endometriosis express altered levels of several endometrial progesterone target genes which may be due to the abnormal expression and/or function of progesterone receptors and/or chaperone proteins, as well as inflammation, genetics, and epigenetics. MiRNAs are a class of epigenetic modulators proposed to play a role in endometriosis pathophysiology, including the modulation of progesterone signaling. In this paper, we summarize the role of progesterone receptors and progesterone signaling in endometriosis pathophysiology, review miRNAs, which are over-expressed in endometriosis tissues and fluids, and follow this with a discussion on the potential regulation of key progesterone signaling components by these miRNAs, concluding with suggestions for future research endeavors in this area.


Assuntos
Endometriose , Infertilidade , MicroRNAs , Endometriose/metabolismo , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Progesterona , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo
8.
Proc Natl Acad Sci U S A ; 119(15): e2117004119, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35394864

RESUMO

SignificanceThe steroid hormone progesterone is highly involved in different physiological-pathophysiological processes, including bone formation and cancer progression. Understanding the working mechanisms, especially identifying the receptors of progesterone hormones, is of great value. In the present study, we identified GPR126 as a membrane receptor for both progesterone and 17-hydroxyprogesterone and triggered its downstream G protein signaling. We further characterized the residues of GPR126 that interact with these two ligands and found that progesterone promoted the progression of a triple-negative breast cancer model through GPR126-dependent Gi-SRC signaling. Therefore, developing antagonists targeting GPR126-Gi may provide an alternative therapeutic option for patients with triple-negative breast cancer.


Assuntos
Progesterona , Receptores Acoplados a Proteínas G , Receptores de Progesterona , Neoplasias de Mama Triplo Negativas , 17-alfa-Hidroxiprogesterona/metabolismo , Linhagem Celular Tumoral , Humanos , Progesterona/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
9.
Elife ; 112022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35244538

RESUMO

The establishment of pregnancy in human necessitates appropriate decidualization of stromal cells, which involves steroids regulated periodic transformation of endometrial stromal cells during the menstrual cycle. However, the potential molecular regulatory mechanism underlying the initiation and maintenance of decidualization in humans is yet to be fully elucidated. In this investigation, we document that SOX4 is a key regulator of human endometrial stromal cells decidualization by directly regulating FOXO1 expression as revealed by whole genomic binding of SOX4 assay and RNA sequencing. Besides, our immunoprecipitation and mass spectrometry results unravel that SOX4 modulates progesterone receptor (PGR) stability through repressing E3 ubiquitin ligase HERC4-mediated degradation. More importantly, we provide evidence that dysregulated SOX4-HERC4-PGR axis is a potential cause of defective decidualization and recurrent implantation failure in in-vitro fertilization (IVF) patients. In summary, this study evidences that SOX4 is a new and critical regulator for human endometrial decidualization, and provides insightful information for the pathology of decidualization-related infertility and will pave the way for pregnancy improvement.


Assuntos
Decídua , Receptores de Progesterona , Decídua/metabolismo , Endométrio , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Gravidez , Estabilidade Proteica , Receptores de Progesterona/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Células Estromais/metabolismo
10.
Gen Comp Endocrinol ; 321-322: 114025, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35292264

RESUMO

Nuclear progestin receptor (PGR), which is induced in the follicles destined to undergo ovulation, is believed to be obligatory for rupture of the follicles during ovulation in vertebrates. Studies in some mammals and teleost medaka have revealed the outline of the central signaling pathway that leads to the PGR expression in the preovulatory follicles at ovulation. In this review, we summarize the current knowledge on what signaling mediators are involved in the LH-induced follicular expression of PGR at ovulation in these animals. LH-inducibility of follicular PGR expression is conserved. In both group of animals, activation of the LH receptor on the granulosa cell surface with LH commonly results in the increase of intracellular cAMP levels, while the downstream signaling cascades activated by high level of cAMP are totally different between mice and medaka. PGR is currently presumed to be induced via PKA/CREB-mediated transactivation and ERK1/2-dependent signaling in mice, but the receptor is induced via EPAC/RAP and AKT/CREB pathways in the teleost medaka. The differences and similarities in the signaling pathways for PGR expression between them is discussed from comparative and evolutionary aspects. We also discussed questions concerning PGR expression and its regulation needed to be investigated in future.


Assuntos
Oryzias , Receptores de Progesterona , Animais , Feminino , Células da Granulosa/metabolismo , Mamíferos/metabolismo , Camundongos , Oryzias/metabolismo , Ovulação/fisiologia , Congêneres da Progesterona , Progestinas/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Transdução de Sinais , Esteroides/metabolismo
11.
Nat Commun ; 13(1): 1101, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35232969

RESUMO

Female subfertility is highly associated with endometriosis. Endometrial progesterone resistance is suggested as a crucial element in the development of endometrial diseases. We report that MIG-6 is downregulated in the endometrium of infertile women with endometriosis and in a non-human primate model of endometriosis. We find ERBB2 overexpression in the endometrium of uterine-specific Mig-6 knockout mice (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6d/d mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6d/d mice revert to their normal expression in Mig-6d/dErbb2d/d mice. Together, our results demonstrate that ERBB2 overexpression in endometrium with MIG-6 deficiency causes endometrial progesterone resistance and a nonreceptive endometrium in endometriosis-related infertility, and ERBB2 targeting reverses these effects.


Assuntos
Endometriose , Infertilidade Feminina , Peptídeos e Proteínas de Sinalização Intracelular , Receptor ErbB-2 , Doenças Uterinas , Animais , Endometriose/genética , Endometriose/metabolismo , Endométrio/anormalidades , Endométrio/metabolismo , Feminino , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Progesterona/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Doenças Uterinas/genética , Doenças Uterinas/metabolismo
12.
Sci Rep ; 12(1): 4038, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35260587

RESUMO

Breast cancer is the leading cause of cancer death among women. Triple-negative breast cancer (TNBC) has a poor prognosis and frequently relapses early compared with other subtypes. The Cold Atmospheric Plasma (CAP) is a promising therapy for prognostically poor breast cancer such as TNBC. The Canady Helios Cold Plasma (CHCP) induces cell death in the TNBC cell line without thermal damage, however, the mechanism of cell death by CAP treatment is ambiguous and the mechanism of resistance to cell death in some subset of cells has not been addressed. We investigate the expression profile of 48 apoptotic and 35 oxidative gene markers after CHCP treatment in six different types of breast cancer cell lines including luminal A (ER+ PR+/-HER2-), luminal B (ER+PR+/-HER2+), (ER-PR-HER2+), basal-like: ER-PR-HER2- cells were tested with CHCP at different power settings and at 4 different incubation time. The expression levels of the gene markers were determined at 4 different intervals after the treatment. The protein expression of BCL2A1 was only induced after CHCP treatment in TNBC cell lines (p < 0.01), whereas the HER2-positive and ER, PR positive cell lines showed little or no expression of BCL2A1. The BCL2A1 and TNF-alpha expression levels showed a significant correlation within TNBC cell lines (p < 0.01). Silencing BCL2A1 mRNA by siRNA increased the potency of the CHCP treatment. A Combination of CHCP and CPI203, a BET bromodomain inhibitor, and a BCL2A1 antagonist increased the CHCP-induced cell death (p < 0.05). Our results revealed that BCL2A1 is a key gene for resistance during CHCP induced cell death. This resistance in TNBCs could be reversed with a combination of siRNA or BCL2A1 antagonist-CHCP therapy.


Assuntos
Neoplasias da Mama , Gases em Plasma , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/metabolismo , Morte Celular , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , Gases em Plasma/farmacologia , RNA Interferente Pequeno/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
13.
Cells ; 11(6)2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35326450

RESUMO

Endometrial cancer (EC) is characterized by high estrogen levels unopposed by progesterone. Treatment with progestins is standard for early EC, but the response to progestins is dependent on progesterone receptor (PGR) expression. Here, we show that the expression of PGR in endometrial epithelial cells is dependent on ARID1A, a DNA-binding subunit of the SWI/SNF chromatin-remodeling complex that is commonly mutated in EC. In endometrial epithelial cells with estrogen receptor overexpression, we find that ARID1A promotes estrogen signaling and regulates common gene expression programs. Normally, endometrial epithelial cells expressing estrogen receptors respond to estrogen by upregulating the PGR. However, when ARID1A expression is lost, upregulation of PGR expression is significantly reduced. This phenomenon can also occur following the loss of the SWI/SNF subunit BRG1, suggesting a role for ARID1A- and BRG1-containing complexes in PGR regulation. We find that PGR is regulated by a bivalent promoter, which harbors both H3K4me3 and H3K27me3 histone tail modifications. H3K27me3 is deposited by EZH2, and inhibition of EZH2 in the context of ARID1A loss results in restoration of estrogen-induced PGR expression. Our results suggest a role for ARID1A deficiency in the loss of PGR in late-stage EC and a therapeutic utility for EZH2 inhibitors in this disease.


Assuntos
Histonas , Proteínas Nucleares , Estrogênios/farmacologia , Feminino , Humanos , Proteínas Nucleares/metabolismo , Progestinas/farmacologia , Receptores de Progesterona/metabolismo
14.
Breast ; 63: 24-28, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35279509

RESUMO

BACKGROUND: The benefit of endocrine therapy for patients with estrogen receptor (ER)-low (1%-10%) positive breast cancer is a matter for debate. We aimed to compare the clinical characteristics and survival outcome of ER-low patients with ER-high (>10%) positive patients and ER-negative patients. METHODS: From the breast cancer database of our institution, we identified 5466 patients with known ER status who were diagnosed with early-stage breast cancer between January 2008 and December 2016. Variables associated with initiation of endocrine therapy were identified using multivariate logistic regression model. According to ER status, all patients were classified into ER-low (1%-10%), ER-high (>10%) and ER-negative subgroups. Fine and Gray competing risks regression was performed to compare the survival outcome of three subgroups. RESULTS: Age at diagnosis, ER status and progesterone receptor (PR) status were identified as correlates of initiation of endocrine therapy. ER-low patients were more likely to have advanced, PR-negative, human epidermal growth factor receptor 2 (HER2)-positive or grade Ⅲ disease compared to ER-high patients. Similar to ER-negative patients, ER-low patients presented increased rate of locoregional recurrence (LRR), distant recurrence (DR) and breast cancer mortality (BCM) than ER-high patients. Endocrine therapy showed nonsignificant trends toward lower LRR, DR and BCM in ER-low patients. CONCLUSION: Similar to ER-negative patients, ER-low patients had more aggressive clinical characteristics and worse survival outcome than ER-high patients. ER-low patients appeared to benefit less from endocrine therapy. Randomized studies are needed to further explore the endocrine responsiveness of ER-low patients.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Mama/metabolismo , Feminino , Humanos , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
15.
Breast Cancer Res ; 24(1): 22, 2022 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-35307014

RESUMO

BACKGROUND: There is an increasing interest in HER2-low breast cancer with promising data from clinical trials using novel anti-HER2 antibody-drug conjugates. We explored the differences in clinicopathological characteristics and survival outcomes between HER2-low and HER2-IHC 0 breast cancer. METHODS: Using nationwide data from the Korean Breast Cancer Registry between 2006 and 2011, 30,491 patients with stages I to III breast cancer were included in the analysis: 9,506 (31.2%) in the HER2-low group and 20,985 (68.8%) in the HER2-IHC 0 group. Kaplan-Meier and Cox proportional hazards regression survival analysis were used to compare breast cancer-specific survival between the two groups. RESULTS: HER2-low breast cancer was more frequent in patients with hormone receptor-positive breast cancer than in those with triple-negative breast cancer. In patients with hormone receptor-positive breast cancer, HER2-low breast cancer was associated with fewer T4 tumors, higher histological grade, and a negative lymphatic invasion. In patients with triple-negative breast cancer, HER2-low breast cancer was associated with a high lymph node ratio and positive lymphatic invasion. HER2-low breast cancer was significantly associated with a lower Ki-67 labeling index. No significant difference was observed in overall survival between the two groups. HER2-low breast cancer showed significantly better breast cancer-specific survival than HER2-IHC 0 breast cancer, regardless of the hormone receptor status. In multivariate analysis, the impact of low HER2 expression on breast cancer-specific survival was significant only in triple-negative breast cancer (HRs, 0.68; 95% CI, 0.49-0.93; P = 0.019). CONCLUSIONS: These findings suggest that the biology and clinical impact of low HER2 expression can differ according to the hormone receptor status and support the need for further investigation on the understanding of the biology of HER2-low breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Hormônios , Humanos , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , República da Coreia/epidemiologia
16.
PLoS One ; 17(3): e0265417, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35344552

RESUMO

The incidence of breast cancer is increasing in low- and middle-income countries, including Thailand. However, its molecular immunohistochemical (M-IHC) subtypes have not been summarized in a population-based cancer registry. Thus, we aimed to estimate the breast cancer incidence and trends based on the hormone receptor and human epidermal growth factor receptor 2 (HER2) status. This cross-sectional study included 2,883 women diagnosed with primary invasive breast cancer between 2009 and 2018 from the Songkhla Cancer Registry. After imputing the missing values of estrogen receptor (ER), progesterone receptor (PR), and HER2 status, the cases were classified into four subtypes: HR+/HER2-, HR+/HER2+, HR-/HER2-, and HR-/HER2+. The age-specific incidence rate of 5-year age groups and age-standardized incidence rate (ASR) were calculated. An age-period-cohort (APC) model was used to describe the effects of age, birth cohort, and period of diagnosis. Finally, the incidence trends were extrapolated to 2030 based on the APC and joinpoint models. The results showed, HR+/HER2- had the highest ASR in breast cancer. The incidence trends of HR+/HER2- and HR+/HER2+ increased with an annual percent change of 5.4% (95%CI: 2.5% to 8.3%) and 10.1% (95%CI: 4.9% to 15.5%), respectively. The rate ratio was high in the younger generation and recent period of diagnosis. The joinpoint and APC model projections showed that the ASR of HR+/HER2- would reach 30.0 and 29.2 cases per 100,000 women, while ASR of the HR+/HER2+ would reach 8.8 and 10.4 cases per 100,000 women in 2030. On the other hand, the incidence trends of the HR-/HER2- and HR-/HER2+ subtypes were stable. The rising trends of HR-positive and a part of HER2-positive breast cancer forecast a dynamicity of the future health care budgeting, resource allocation, and provision of facilities.


Assuntos
Neoplasias da Mama , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Estudos Transversais , Feminino , Humanos , Incidência , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Tailândia/epidemiologia
17.
Zhonghua Yi Xue Za Zhi ; 102(10): 741-744, 2022 Mar 15.
Artigo em Chinês | MEDLINE | ID: mdl-35280019

RESUMO

To investigate the effect of progesterone receptor (PR) on the efficacy of first-line aromatase inhibitor (AI) endocrine therapy and progression-free survival (PFS) in patients with estrogen receptor (ER) positive HER-2 negative advanced breast cancer. The clinical data of 198 patients with advanced breast cancer treated in Henan Cancer Hospital from January 2014 to October 2019 were collected. The Chi-square test was used to compare the difference between the two groups, and the Cox regression model was used to analyze the related prognostic factors. The median progression-free survival time ((PFS)) of PR+and PR- patients were 12.5 months and 9.0 months, respectively, and the difference was statistically significant (P=0.004). The clinical benefit rate (CBR) was 81.1% and 63.1%, respectively, and the difference was not statistically significant (P<0.001). PR is an independent prognostic factor of first-line AI endocrine therapy in ER-positive HER-2-negative patients. PR+type breast cancer has a better response to first-line AI endocrine therapy and longer PFS time than PR- type advanced breast cancer.


Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Receptores de Progesterona/metabolismo , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Taxa de Sobrevida
18.
J Transl Med ; 20(1): 72, 2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-35123491

RESUMO

Lung cancer remains a huge challenge to public health because of its high incidence and mortality, and lung adenocarcinoma (LUAD) is the main subtype of lung cancer. Hypoxia-induced vascular endothelial growth factor (VEGF) release and angiogenesis have been regarded as critical events in LUAD carcinogenesis. In the present study, membrane progesterone receptor α (mPRα) is deregulated within LUAD tissue samples; increased mPRα contributes to a higher microvessel density (MVD) in LUAD tissues. mPRα knockdown in A549 and PC-9 cells significantly inhibited STAT3 phosphorylation, as well as HIF1α and VEGF protein levels, decreasing cancer cell migration and invasion. The in vivo xenograft model further confirmed that mPRα enhanced the aggressiveness of LUAD cells. Furthermore, mPRα knockdown significantly inhibited hypoxia-induced upregulation in HIF1α and VEGF levels, as well as LUAD cell migration and invasion. Under the hypoxic condition, conditioned medium (CM) derived from mPRα knockdown A549 cells, namely si-mPRα-CM, significantly inhibited HUVEC migration and tube formation and decreased VEGF level in the culture medium. In contrast, CM derived from mPRα-overexpressing A549 cells, namely mPRα-CM, further enhanced HUVEC migration and tube formation and increased VEGF level under hypoxia, which was partially reversed by STAT3 inhibitor Stattic. In conclusion, in LUAD cells, highly expressed mPRα enhances the activation of cAMP/JAK/STAT3 signaling and increases HIF1α-induced VEGF secretion into the tumor microenvironment, promoting HUVEC migration and tube formation under hypoxia.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Animais , Hipóxia Celular , Humanos , Neoplasias Pulmonares/patologia , Neovascularização Patológica/patologia , Progesterona/farmacologia , Receptores de Progesterona/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
PLoS One ; 17(2): e0263222, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35113931

RESUMO

Breast cancer is a major health problem worldwide. Analysis of breast cancer epidemiology in emerging countries enables assessment of prognostic factors, cancer care quality, and the equity of resource distribution. We aimed to estimate the overall (OS) and cancer-specific survival (SS) of breast cancer patients in the northeastern Brazilian state of Sergipe to identify independent prognostic factors. We analyzed a cohort for the factors age at diagnosis, place of residence, time to treatment, staging, and molecular classification, using the Kaplan-Meier method, log-rank test, Pearson's chi-squared test and Cox regression model. The outcome was the vital status at the end of the study. Our analysis showed an OS probability of 0.72 and an SS probability of 0.75. In multivariate analysis, time to treatment within 60 days, stage IV, and triple-negative classification remained independent prognostic factors for both OS [unadjusted hazard ratio (HRp) 1.50 (1.21; 1.86), HRp 16.56 (8.35; 32.85), and HRp 2.73 (1.73; 4.29), respectively] and SS [HRp 1.43 (1.13; 1.81), HRp 20.53 (9.45; 44.56), and HRp 3.14 (1.88; 5.26), respectively]. Better survival was demonstrated for the following patients: those receiving their first treatment after 60 days, with an OS of 52.5 months (51.2; 53.8) and SS of 53.5 months (52.3; 54.7); stage I patients, with an OS of 58.8 months (57.7; 60.0) and SS of 59.2 months (58.1; 60.3); patients without nodal metastasis, with an OS of 54.2 months (53.0; 55.4) and SS of 55.6 months (54.5; 56.7); and patients with luminal A classification, with an OS of 56.8 months (55.0; 58.5) and SS of 57.8 months (56.2; 59.4). This study identified independent prognostic factors and that OS and SS were lower for patients from Sergipe than for patients in high-income areas. Therefore, determining the profiles of breast cancer patients in this population will inform specific cancer care.


Assuntos
Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/mortalidade , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
20.
Breast ; 62: 75-83, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35131646

RESUMO

BACKGROUND: The phase IIIb CompLEEment-1 study evaluated ribociclib plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Outcomes were investigated in the following subgroups: central nervous system (CNS) metastases, prior chemotherapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, and visceral metastases plus prior chemotherapy for advanced disease or ECOG PS 2. PATIENTS AND METHODS: Patients with HR+, HER2- ABC without prior hormonal treatment for advanced disease received oral ribociclib (600 mg once daily, 3 weeks on/1 week off) plus letrozole (2.5 mg once daily, continuous). Primary endpoint was safety/tolerability, assessed via occurrence of adverse events (AEs); key secondary endpoints included time to progression (TTP), overall response rate, and clinical benefit rate. RESULTS: 51 patients had CNS metastases, 194 received prior chemotherapy for advanced disease, 112 had ECOG PS 2, 146 had visceral metastases plus prior chemotherapy, and 77 had visceral metastases plus ECOG PS 2. Safety results were consistent with those in the overall CompLEEment-1 population; no new safety concerns were identified. The AE profile was manageable with low rates of discontinuations due to AEs. TTP in patients with CNS metastases was consistent with the overall study population and shorter for other patient subgroups. Each patient subgroup achieved meaningful clinical benefit from treatment, consistent with the overall population. CONCLUSION: These findings confirm the clinical benefit of ribociclib plus endocrine therapy in high-risk patient subgroups of clinical interest commonly underrepresented in clinical trials.


Assuntos
Neoplasias da Mama , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Hormônios/uso terapêutico , Humanos , Letrozol , Purinas , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
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