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1.
Breast Cancer Res ; 24(1): 46, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35821051

RESUMO

BACKGROUND: Locally advanced breast cancer (LABC), the most aggressive form of the disease, is a serious threat for women's health worldwide. The AU-rich RNA-binding factor 1 (AUF1) promotes the formation of chemo-resistant breast cancer stem cells. Thereby, we investigated the power of AUF1 expression, in both cancer cells and their stromal fibroblasts, as predictive biomarker for LABC patients' clinical outcome following neoadjuvant treatment. METHODS: We have used immunohistochemistry to assess the level of AUF1 on formalin-fixed paraffin-embedded tissues. Immunoblotting was utilized to show the effect of AUF1 ectopic expression in breast stromal fibroblasts on the expression of various genes both in vitro and in orthotopic tumor xenografts. Cytotoxicity was evaluated using the WST1 assay, while a label-free real-time setting using the xCELLigence RTCA technology was utilized to assess the proliferative, migratory and invasive abilities of cells. RESULTS: We have shown that high AUF1 immunostaining (≥ 10%) in both cancer cells and their adjacent cancer-associated fibroblasts (CAFs) was significantly associated with higher tumor grade. Kaplan-Meier univariate analysis revealed a strong correlation between high AUF1 level in CAFs and poor patient's survival. This correlation was highly significant in patients with triple negative breast cancer, who showed poor disease-free survival (DFS) and overall survival (OS). High expression of AUF1 in CAFs was also associated with poor OS of ER+/Her2- patients. Similarly, AUF1-positive malignant cells tended to be associated with shorter DFS and OS of ER+/Her2+ patients. Interestingly, neoadjuvant therapy downregulated AUF1 to a level lower than 10% in malignant cells in a significant number of patients, which improved both DFS and OS. In addition, ectopic expression of AUF1 in breast fibroblasts activated these cells and enhanced their capacity to promote, in an IL-6-dependent manner, the epithelial-to-mesenchymal transition and stemness processes. Furthermore, these AUF1-expressing cells enhanced the chemoresistance of breast cancer cells and their growth in orthotopic tumor xenografts. CONCLUSIONS: The present findings show that the CAF-activating factor AUF1 has prognostic/predictive value for breast cancer patients and could represent a great therapeutic target in order to improve the precision of cancer treatment.


Assuntos
Neoplasias da Mama , Ribonucleoproteínas Nucleares Heterogêneas Grupo D , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinogênese/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Fibroblastos/metabolismo , Ribonucleoproteína Nuclear Heterogênea D0 , Ribonucleoproteínas Nucleares Heterogêneas Grupo D/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo D/metabolismo , Humanos , Prognóstico
2.
Breast Cancer Res ; 22(1): 49, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32414408

RESUMO

BACKGROUND: Most breast cancer-associated fibroblasts (CAFs) are active and important cancer-promoting cells, with significant impact on patient prognosis. Therefore, we investigated here the role of the protein kinase ATR in breast stromal fibroblasts in the prognosis of locally advanced breast cancer patients. METHODS: We have used immunohistochemistry to assess the level of ATR in breast cancer tissues and their adjacent normal tissues. Immunoblotting as well as quantitative RT-PCR were utilized to show the role of breast cancer cells and IL-6 as well as AUF-1 in downregulating ATR in breast stromal fibroblasts. Engineered human breast tissue model was also used to show that ATR-deficient breast stromal fibroblasts enhance the growth of breast cancer cells. RESULTS: We have shown that the protein kinase ATR is downregulated in cancer cells and their neighboring CAFs in breast cancer tissues as compared to their respective adjacent normal tissues. The implication of cancer cells in ATR knockdown in CAFs has been proven in vitro by showing that breast cancer cells downregulate ATR in breast fibroblasts in an IL-6/STAT3-dependent manner and via AUF-1. In another cohort of 103 tumors from locally advanced breast cancer patients, we have shown that absence or reduced ATR expression in tumoral cells and their adjacent stromal fibroblasts is correlated with poor overall survival as well as disease-free survival. Furthermore, ATR expression in CAFs was inversely correlated with tumor recurrence and progression. CONCLUSION: ATR downregulation in breast CAFs is frequent, procarcinogenic, and correlated with poor patient survival.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/biossíntese , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Recidiva Local de Neoplasia/patologia , Células Estromais/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Células Estromais/patologia
3.
Mol Carcinog ; 59(9): 1041-1051, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32537818

RESUMO

Triple-negative breast cancer (TNBC) is a very aggressive subtype with high recurrence rate and no molecular targets for therapies. This subtype is characterized by high expression/secretion of the proinvasive/metastatic interleukin-6 (IL-6) cytokine. In the present study, we have shown that tocilizumab inhibits the IL-6/STAT3 signaling and suppresses the cancer/inflammatory epigenetic IL-6/STAT3/NF-κB positive feedback loop. Furthermore, tocilizumab inhibited the proliferative and the migratory/invasiveness capacities as well as the epithelial-to-mesenchymal transition (EMT) process in TNBC cells. Importantly, tocilizumab suppressed the stemness-related characteristics of TNBC cells, through the inhibition of the Wnt/ß-catenin breast cancer stem cell-related pathway. Additionally, we have shown that tocilizumab suppresses the paracrine activation of normal breast stromal fibroblasts to myofibroblats. Moreover, tocilizumab sensitized TNBC cells to the cytotoxic effect of cisplatin in vitro. Furthermore, pharmacological inhibition of IL-6 by tocilizumab had great inhibitory effect on tumor growth and the EMT process in humanized orthotopic breast tumors in mice. In addition, tocilizumab potentiated the proapoptotic effect of cisplatin in humanized breast tumors. Together, these findings indicate that tocilizumab can suppress the prometastatic capacity of TNBC cells and enhances the cytotoxic effect of cisplatin against these cells. Therefore, tocilizumab could be of great therapeutic value for these hard-to-treat TNBC patients.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , NF-kappa B/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética , beta Catenina/metabolismo
4.
Oncology ; 98(3): 168-173, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31918425

RESUMO

BACKGROUND: There is a paucity of literature examining the impact of timing of surgery after neoadjuvant chemotherapy. OBJECTIVE: This study aimed to analyze the impact of the time taken to initiate surgical treatment following completion of neoadjuvant chemotherapy on patients' outcomes by evaluating their pathological response, overall survival (OS), and disease-free survival (DFS). METHODS: This is a retrospective review of 611 patients diagnosed with stage II and III breast cancer that received neoadjuvant chemotherapy and surgery between January 2004 and December 2014. The data was collected from a prospectively gathered registry. The patients were stratified into three cohorts according to the time of surgery after neoadjuvant chemotherapy: <4 weeks, 4-7 weeks, or ≥8 weeks. Outcomes were assessed using Kaplan-Meier curves, and the variables were compared using log-rank statistics. RESULTS: The 5-year OS rate was 89.6% and the 5-year DFS rate was 74%. OS and DFS were not significantly different when stratified according to timing of surgery; however, the trends of OS and DFS were poor when surgery was delayed for ≥8 weeks. Median OS and median DFS have not yet been reached. Of the 17% of patients that had surgery after ≥8 weeks, 12.9% had pathological complete response (pCR), while among those that received surgery 4-7 weeks and <4 weeks after neoadjuvant chemotherapy, 26% and 21% had pCR, respectively (p = 0.02). ER+/HER-2+ patients had a statistically significant decrease in pCR if surgery was performed after ≥8 weeks. CONCLUSION: Our patients showed improved pCR if surgery was performed within 8 weeks, especially for ER+/HER-2+ patients. All patients had better OS and DFS trends if surgery was performed between 4 and 7 weeks after neoadjuvant chemotherapy.


Assuntos
Neoplasias da Mama/terapia , Mastectomia , Terapia Neoadjuvante , Tempo para o Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Mastectomia/efeitos adversos , Mastectomia/mortalidade , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Estadiamento de Neoplasias , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto Jovem
5.
Int J Cancer ; 145(3): 830-841, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30719702

RESUMO

Breast cancer remains the second cause of tumor-related mortality in women worldwide mainly due to chemoresistance and metastasis. The chemoresistance and metastasis are attributed to a rare subpopulation with enriched stem-like characteristics, thus called Cancer Stem Cells (CSCs). We have previously reported aberrant expression of the actin-bundling protein (fascin) in breast cancer cells, which enhances their chemoresistance, metastasis and enriches CSC population. The intracellular mechanisms that link fascin with its downstream effectors are not fully elucidated. Here, loss and gain of function approaches in two different breast cancer models were used to understand how fascin promotes disease progression. Importantly, findings were aligned with expression data from actual breast cancer patients. Expression profiling of a large breast cancer dataset (TCGA, 530 patients) showed statistically significant correlation between fascin expression and a key adherence molecule, ß1 integrin (ITGB1). In vitro manipulation of fascin expression in breast cancer cells exhibited its direct effect on ITGB1 expression. Fascin-mediated regulation of ITGB1 was critical for several breast cancer cell functions including adhesion to different extracellular matrix, self-renewability and chemoresistance. Importantly, there was a significant relationship between fascin and ITGB1 co-expression and short disease-free as well as overall survival in chemo-treated breast cancer patients. This novel role of fascin effect on ITGB1 expression and its outcome on cell self-renewability and chemoresistance strongly encourages for dual targeting of fascin-ITGB1 axis as a therapeutic approach to halt breast cancer progression and eradicate it from the root.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Transporte/biossíntese , Integrina beta1/biossíntese , Proteínas dos Microfilamentos/biossíntese , Células-Tronco Neoplásicas/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Integrina beta1/genética , Integrina beta1/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Análise de Sobrevida , Regulação para Cima
6.
Mol Cancer ; 14: 149, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26245467

RESUMO

BACKGROUND: The T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. However, the mechanism that regulates PD-L1 expression in this group of patients is still not well-identified. METHODS: We have used loss and gain of function gene manipulation approach, multi-parametric flow cytometry, large scale gene expression dataset analysis and immunohistochemistry of breast cancer tissue sections. RESULTS: Induction of epithelial to mesenchymal transition (EMT) in human mammary epithelial cells upregulated PD-L1 expression, which was dependent mainly on the activation of the PI3K/AKT pathway. Interestingly, gene expression signatures available from large cohort of breast tumors showed a significant correlation between EMT score and the PD-L1 mRNA level (p < 0.001). Strikingly, very strong association (p < 0.0001) was found between PD-L1 expression and claudin-low subset of breast cancer, which is known to have high EMT score. On the protein level, significant correlation was found between PD-L1 expression and standard markers of EMT (p = 0.005) in 67 breast cancer patients. Importantly, specific downregulation of PD-L1 in claudin-low breast cancer cells showed signs of EMT reversal as manifested by CD44 and Vimentin downregulation and CD24 upregulation. CONCLUSIONS: We have demonstrated a bidirectional effect between EMT status and PD-L1 expression especially in claudin-low subtype of breast cancer cells. Our findings highlights the potential dual benefit of anti-PD-L1 particularly in this subset of breast cancer patients that will likely benefit more from anti-PD-L1 targeted therapy as well as in monitoring biological changes upon treatment.


Assuntos
Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Animais , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Claudinas/genética , Claudinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Transcriptoma
7.
BMC Cancer ; 14: 788, 2014 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-25351244

RESUMO

BACKGROUND: Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death amongst women worldwide. The risk factors of this disease are numerous, and their prevalence varies between racial and ethnic groups as well as geographical regions. Therefore, we sought to delineate the association of socio-demographic, reproductive and life-style related risk factors with breast cancer in the Arab population. METHODS: Unmatched case-control study was conducted in the kingdom of Saudi Arabia using 534 cases of histologically confirmed breast cancer and 638 controls. Controls were randomly selected from primary health care visits and were free of breast cancer. Unconditional logistic regression analysis was performed to estimate odds ratios (ORs) and to examine the predictive effect of each factor on risk for BC. All study participants were interviewed by trained interviewers at hospital (cases) or at primary health care centers (controls). RESULTS: A total of 1172 women were eligible for this study, of which 281 (24.0%) were aged ≤35 years, 22.9% illiterate, 43.6% employed, 89.5% married, and 38.1% were obese. Grade III tumors constituted 38.4% of cases. Tumor stage I was 7.5%; II, 50.7%; II, 30.9%; IV, 11.1%. We have shown strong association between breast cancer among Arab females and obesity (OR =2.29, 95% CI 1.68-3.13), positive family history of breast cancer (OR =2.31, 95% CI 1.60 - 3.32), the use of hormonal replacement therapy (OR =2.25, 95% CI 1.65 - 3.08), post-menopause (OR =1.72, 95% CI 1.25 - 2.38), lack of education (OR =9.09, 95% CI 5.88 - 14.29), and never breastfeed (OR =1.89, 95% CI 1.19 - 2.94). CONCLUSION: These results indicate the presence of classical risk factors established in the western countries, and also some specific ones, which may result from genetic and/or environmental factors. Thereby, these findings will be of great value to establish adequate evidence-based awareness and preventative measures in the Arab world.


Assuntos
Árabes , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Obesidade/complicações , Adulto , Idoso , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Humanos , Estilo de Vida , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Razão de Chances , Fatores de Risco , Arábia Saudita/epidemiologia , Adulto Jovem
8.
BMC Cancer ; 14: 830, 2014 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-25403427

RESUMO

BACKGROUND: BRCA1 promoter methylation has been detected in DNA from peripheral blood cells of both breast cancer patients and cancer-free females. However, the pathological significance of this epigenetic change in white blood cells (WBC) remains an open question. In this study, we hypothesized that if constitutional BRCA1 methylation reflects an elevated risk for developing breast cancer (BC), WBC that harbor methylated BRCA1 in both cancer-free females and BC patients should exhibit similar molecular changes. METHODS: BRCA1 promoter methylation was examined by methylation-specific PCR in WBC from 155 breast cancer patients and 143 cancer-free females. The Human Breast Cancer EpiTect Methyl II Signature PCR Array and The Human Breast Cancer RT2 Profiler™ PCR Array were used to study the methylation status and the expression profile of several breast cancer-related genes, respectively. In addition, we used label-free MS-based technique to study protein expression in plasma. RESULTS: We have shown that 14.2% of BC patients and 9.1% of cancer-free females (carriers) harbored methylated BRCA1 promoter in their WBC. Interestingly, 66.7% of patients harbored methylated BRCA1 promoter in both WBC and tumors. Importantly, we have shown the presence of epigenetic changes in 9 other BC-related genes in WBC of both patients and carriers. Additionally, BRCA1 and 15 other important cancer -related genes were found to be differentially expressed in WBC from patients and carriers as compared to controls. Furthermore, we have shown that the carriers exhibited a unique plasma protein pattern different from those of BC patients and controls, with 10 proteins similarly differentially expressed in patients and carriers as compared to controls. CONCLUSIONS: The present results suggest the presence of a strong link between aberrant methylation of the BRCA1 promoter in WBC and breast cancer -related molecular changes, which indicate the potential predisposition of the carriers for developing breast cancer. This informs the potential use of the aberrant methylation of BRCA1 promoter in WBC as a powerful non-invasive molecular marker for detecting predisposed individuals at a very early age.


Assuntos
Proteína BRCA1/genética , Metilação de DNA , Leucócitos/metabolismo , Regiões Promotoras Genéticas , Transcriptoma , Adolescente , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Análise por Conglomerados , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Heterozigoto , Humanos , Glândulas Mamárias Humanas/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Adulto Jovem
9.
Oncol Lett ; 28(3): 429, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39049989

RESUMO

The present study aimed to clarify the prognostic role of the pre-treatment neutrophil-to-lymphocyte ratio (NLR) for the response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC). Due to conflicting results in currently available data, the specific focus of the present study was on evaluating the associations between the pre-treatment NLR and the rate of achieving a pathological complete response (pCR) and survival outcomes. For the present study, data from a cohort of 465 consecutive patients with LABC who underwent NAC at King Feisal Specialist Hospital and Research Center (Riyadh, Saudi Arabia) between 2005 and 2014 were obtained from a prospective BC database and analyzed. Patients were stratified into two groups based on an optimal NLR cut-off determined using the receiver operating characteristic curve. Logistic regression analyses were conducted to assess variables associated with pCR, and Cox regression analyses were used to assess variables associated with survival outcomes. The low pre-treatment NLR group (≤2.2) was found to exhibit a higher likelihood of achieving a pCR (odds ratio, 2.59; 95% CI, 1.52-4.38; P<0.001), along with higher 5-year disease-free survival (DFS) [75.8 vs. 64.9%; hazard ratio (HR), 0.69; 95% CI, 0.50-0.94; P=0.02] and 5-year overall survival (OS; 90.3 vs. 81.9; HR, 0.62; 95% CI, 0.39-0.98; P=0.04) rates compared with those in the high NLR group (>2.2). Sub-group analysis revealed that the observed significance in survival outcomes was driven by the triple-negative BC (TNBC) subgroup. Patients with residual TNBC disease and a high pre-treatment NLR were observed to have lower 5-year DFS (44.4 vs. 75.0%; P=0.02) and 5-year OS (55.9 vs. 84.5%; P=0.055) rates compared with those with residual TNBC disease and a low NLR. To conclude, data from the present study suggest that the pre-treatment NLR can serve as a viable independent prognostic factor for pCR following NAC in patients with LABC and for survival outcomes, particularly for patients with TNBC.

10.
Cell Death Discov ; 10(1): 61, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38296962

RESUMO

Breast cancer (BC) patient who receives chemotherapy for an extended length of time may experience profound repercussions in terms of metastases and clinical outcomes due to the involvement of the epithelial-to-mesenchymal transition (EMT) mechanism and enriched cancer stem cells (CSCs). BC cells that express high levels of lncRNA deleted in lymphocytic leukemia-2 (lncRNA DLEU2) and type I tyrosine kinase-like orphan receptor ROR1 (ROR1) may play roles in the enhanced ability of the activation EMT and CSC induction. Here we find that lncRNA DLEU2 and ROR1 are specifically upregulated in tumor tissues compared to their normal counterparts in TCGA, PubMed GEO datasets, and samples from archived breast cancer tumor tissues. Following chemotherapy, lncRNA DLEU2 and ROR1 were enhanced in BC tumor cells, coupled with the expression of CSCs, EMT-related genes, and BMI1. Mechanistically, ROR1 and lncRNA DLEU2 overexpression led to enhanced tumor cell proliferation, inhibition of apoptosis, cell-cycle dysregulation, chemoresistance, as well as BC cell's abilities to invade, migrate, develop spheroids. These findings imply that the role of lncRNA DLEU2 and ROR1 in BC therapeutic failure is largely attributed to EMT, which is intricately linked to enriched CSCs. In conclusion, our findings indicate that a lncRNA DLEU2 and ROR1-based regulatory loop governs EMT and CSC self-renewal, implying that targeting this regulatory pathway may improve patients' responses to chemotherapy and survival.

13.
Biomedicines ; 10(2)2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35203574

RESUMO

Triple-negative breast cancers (HER2-, ER-, PR-) continue to present a unique treatment challenge and carry unfavorable prognoses. The elucidation of novel therapeutic targets has necessitated the re-evaluation of stratification approaches to best predict prognosis, treatment response and theranostic and prognostic markers. Androgen receptor expression and function have important implications on proliferation, tumor progression, immunity and molecular signaling in breast cancer. Accordingly, there has been increasing support for classification of androgen receptor-negative triple-negative breast cancer or quadruple-negative breast cancer (QNBC). QNBC has unique molecular, signaling and expression regulation profiles, particularly those affected by microRNA regulatory networks. microRNAs are now known to regulate AR-related targets and pathways that are dysregulated in QNBC, including immune checkpoint inhibitors (ICIs), SKP2, EN1, ACSL4 and EGFR. In this review, we explore and define the QNBC tumor subtype, its molecular and clinical distinctions from other subtypes, miRNA dysregulation and function in QNBC, and knowledge gaps in the field. Potential insights into clinical and translational implications of these dysregulated networks in QNBC are discussed.

14.
Immunotherapy ; 14(4): 189-199, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34984928

RESUMO

Introduction: There is evidence for an association between peripheral blood eosinophil count (PBEC) and response to cancer immunotherapy; however, such data is limited in metastatic triple-negative breast cancer (mTNBC). Patients & methods: This report presents patients (n = 14) who received a combination of durvalumab and paclitaxel for mTNBC (NCT02628132). Results: There was a statistically significant correlation (p = 0.028) between an increase in PBEC (>300/mm3) during treatment and response to the combination therapy. Survival analysis showed a statistically significant association between progression-free survival and increased PBEC, after therapy (p = 0.005). A similar trend existed for overall survival, although it did not reach statistical significance (p = 0.167). Conclusion: This is the first study to report on eosinophilia in mTNBC treated with chemoimmunotherapy and supports a role for eosinophils in immunotherapy for mTNBC.


Plain language summary Previous reports have shown that an increase in peripheral blood eosinophil count is associated with a good response to cancer immunotherapy; however, data on this association is limited in a subtype of breast cancer called metastatic triple-negative breast cancer (mTNBC). The eosinophil count in patients who received the combination of an immunotherapeutic agent, durvalumab and a chemotherapeutic agent, paclitaxel, in mTNBC was assessed. There was a statistically significant association between an increase in eosinophils during treatment and the response to therapy. The progression of the disease was slower or less likely to occur in patients with increased eosinophils. This study supports the role of eosinophils in immunotherapy for mTNBC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Eosinófilos/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Eosinófilos/metabolismo , Feminino , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Resultado do Tratamento
15.
Front Oncol ; 12: 877219, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35719957

RESUMO

Background: Active breast cancer-associated fibroblasts (CAFs) play a leading role in breast carcinogenesis through promoting angiogenesis and resistance to therapy. Consequently, these active stromal cells have significant influence on patient outcome. Therefore, we explored here the role of the DNA methyltransferase 1 (DNMT1) protein in CAF-dependent promotion of angiogenesis as well as the prognostic power of DNMT1 level in both cancer cells and their adjacent CAFs in locally advanced breast cancer patients. Methods: We applied immunohistochemistry to evaluate the level of DNMT1 in breast cancer tissues and their adjacent normal counterparts. Quantitative RT-PCR and immunoblotting were performed to investigate the role of DNMT1 in regulating the expression of pro-angiogenic genes in active CAFs and also their response to the DNMT1 inhibitors decitabine (DAC) as well as eugenol. Results: We have shown that DNMT1 controls the pro-angiogenic potential of CAFs both in vitro and in vivo through positive regulation of the expression/secretion of 2 important pro-angiogenic factors VEGF-A and IL-8 as well as their upstream effectors mTOR and HIF-1α. To confirm this, we have shown that these DNMT1-related pro-angiogenic effects were suppressed by 2 DNMT1 inhibitors decitabine and eugenol. Interestingly, in a cohort of 100 tumors from locally advanced breast cancer patients (LABC), we have shown that high expression of DNMT1 in tumor cells and their adjacent stromal fibroblasts is correlated with poor survival of these patients. Conclusion: DNMT1 upregulation in breast stromal fibroblasts promotes angiogenesis via IL-8/VEGF-A upregulation, and correlates well with poor survival of LABC patients.

16.
Int J Womens Health ; 14: 373-384, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309953

RESUMO

Purpose: Obesity is prevalent in Saudi Arabia and is associated with adverse clinical features and poor breast cancer (BC) outcomes. We determined the distribution of body mass index (BMI) and evaluated its association with disease characteristics and outcomes in women with non-metastatic BC. Patients and Methods: We conducted a retrospective analysis of a prospectively collected database of consecutive patients treated for non-metastatic BC between 2002 and 2014. Patients were categorized into the following groups: underweight/normal weight (BMI <25 kg/m2), overweight (BMI 25-29.9 kg/m2), and obese (BMI ≥30 kg/m2). Regression analysis was used to evaluate clinicopathological factors associated with BMI and clinical stage. Results: A total of 2212 patients were enrolled. The median age was 45 years (interquartile range [IQR], 39-52 years), and the median BMI was 30 kg/m2 (IQR, 26-34 kg/m2). Most patients were premenopausal (63.6%), nearly half of the patients had stage III disease, and 11.2% were screen-detected. The prevalence of obesity was 53.4%, with a significant difference between the peri/premenopausal (49.4%) and postmenopausal (61.7%) groups (p < 0.001). Obese patients were more likely to be aged >40 years, be postmenopausal, have a history of oral contraceptive pills, have advanced-stage disease, and have undergone radiation therapy, and were less likely to have human epithelial growth factor 2 (HER2)+ disease than non-obese patients. Premenopausal obese women had fewer hormone receptor-positive and more triple-negative cancers than postmenopausal obese women did. Obesity, non-screening-detected BC, and HER+ status were independent prognostic factors for advanced-stage presentation. Conclusion: The prevalence of obesity and its significant association with advanced BC justify the upscaling of screening services and instituting weight-reduction strategies.

17.
Hematol Oncol Stem Cell Ther ; 15(1): 79-82, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34181897

RESUMO

CDK 4/6 inhibitors, in combination with endocrine therapy, are the standard of care for patients with endocrinesensitive advanced breast cancer. This class of drug, however, is associated with QT prolongation, which serves as a surrogate marker for Torsades de Pointes (TdP), a cause of life-threatening ventricular arrhythmias and sudden cardiac death. The ICH E14 guidance document uses the Bazett formula for reporting of cardio-dynamic and safety ECG data in clinical trials. While there is substantial familiarity with the Bazett (QTcB) formula (QT/(RR) 1/2), the Fridericia (QTcF) formula (QT/(RR) 1/3 ) is preferred in the cancer population as it is often more accurate at heart rate extreme. Accordingly, the Fridericia formula is currently the standard adopted by the FDA when submitting QT data for review. At the King Faisal Specialist Hospital and Research Center, a total of 82 patients with advanced breast cancer, had a baseline ECG on day 1 before the initiation of ribociclib based therapy. Of the enrolled 82 patients, 19 (23%) were initially excluded from receiving ribociclib based due to a prolonged QTc >450ms, however, when the QTc-interval was manually measured and recalculated using Fridericia and Framingham formulae using MDCalC (https://www.mdcalc.com),17 of 19 patients successfully received their treatment without any arrhythmogenic effects. Repeat ECG on day14, and day 1 of cycle 2 demonstrated that none of these patients had QTc exceeding 480 ms. Our data highlights the complexities of evaluating the QT interval in oncology patients and the utility of the Fridericia/Framingham formulae in this population. Given these findings, we recommend the adoption of the Fridericia or Framingham formulae for measurement of QTc in all cancer patients exposed to potentially QT-prolonging cancer therapy.


Assuntos
Neoplasias da Mama , Síndrome do QT Longo , Humanos , Feminino , Eletrocardiografia , Síndrome do QT Longo/diagnóstico , Frequência Cardíaca/fisiologia
18.
Breast Care (Basel) ; 16(3): 307-311, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34248473

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors have been a significant breakthrough in the management of hormone receptor-positive, HER2-negative metastatic breast cancer based on the results of several large phase III randomized trials. The most common reported toxicity is myelosuppression due to disease such as leukopenia, neutropenia, and thrombocytopenia. Other toxicities associated with CDK 4/6 inhibitors include mucositis, fatigue, gastrointestinal side effects, hepatic toxicities, and QTc prolongation. Despite a good toxicity profile in pivotal studies, the increased rates of use in clinical practice may show less prevalent but lethal toxicity such as lung injury. CASE PRESENTATION: Here, we describe a female patient with metastatic hormone receptor-positive/human epidermal growth factor 2-negative breast cancer who developed lung toxicity while on ribociclib. DISCUSSION: Lung injury is a possible side effect of CDK 4/6 inhibitors and there is an increasing need to understand the management of this side effect.

19.
Genes (Basel) ; 12(4)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918859

RESUMO

Resistance to therapy is a persistent problem that leads to mortality in breast cancer, particularly triple-negative breast cancer (TNBC). MiRNAs have become a focus of investigation as tissue-specific regulators of gene networks related to drug resistance. Circulating miRNAs are readily accessible non-invasive potential biomarkers for TNBC diagnosis, prognosis, and drug-response. Our aim was to use systems biology, meta-analysis, and network approaches to delineate the drug resistance pathways and clinical outcomes associated with circulating miRNAs in TNBC patients. MiRNA expression analysis was used to investigate differentially regulated circulating miRNAs in TNBC patients, and integrated pathway regulation, gene ontology, and pharmacogenomic network analyses were used to identify target genes, miRNAs, and drug interaction networks. Herein, we identified significant differentially expressed circulating miRNAs in TNBC patients (miR-19a/b-3p, miR-25-3p, miR-22-3p, miR-210-3p, miR-93-5p, and miR-199a-3p) that regulate several molecular pathways (PAM (PI3K/Akt/mTOR), HIF-1, TNF, FoxO, Wnt, and JAK/STAT, PD-1/PD-L1 pathways and EGFR tyrosine kinase inhibitor resistance (TKIs)) involved in drug resistance. Through meta-analysis, we demonstrated an association of upregulated miR-93, miR-210, miR-19a, and miR-19b with poor overall survival outcomes in TNBC patients. These results identify miRNA-regulated mechanisms of drug resistance and potential targets for combination with chemotherapy to overcome drug resistance in TNBC. We demonstrate that integrated analysis of multi-dimensional data can unravel mechanisms of drug-resistance related to circulating miRNAs, particularly in TNBC. These circulating miRNAs may be useful as markers of drug response and resistance in the guidance of personalized medicine for TNBC.


Assuntos
Biomarcadores Tumorais/genética , MicroRNA Circulante/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Preparações Farmacêuticas/administração & dosagem , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Metanálise em Rede , Prognóstico , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
20.
Sci Rep ; 11(1): 19154, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580336

RESUMO

Therapeutic anti-PD-L1 antibodies are safe as a monotherapy, albeit with minimal efficacy in triple-negative breast cancer (TNBC). This trial aimed to test the safety and efficacy of Durvalumab and Paclitaxel in metastatic TNBC. In this open-label, one-arm trial, five cycles of weekly paclitaxel were delivered intravenously (IV) concurrent with Durvalumab that was given IV every 2 weeks. The combination was preceded by one cycle of paclitaxel alone, for immunological priming, followed by Durvalumab solo until disease progression or unacceptable toxicity. Between 2017 and 2019, 14 patients received at least one cycle of the combination therapy. The therapy was safe with no-dose limiting toxicity, except one case of skin lesions. Adverse events (AEs) were reported in 71% of patients, and there was no death due to the combination therapy. Regardless of grade, the most common AEs were headache and peripheral neuropathy, as each happened in four patients (29%), followed by fatigue and skin rash in three patients (21%) each. Grade 3/4 AEs were experienced by three patients (21%), with the most common being headache and anemia, which happened in two patients (14%). The confirmed objective response rate (ORR) was observed in five patients with a median duration of 10.0 months. Median Progression-free survival (PFS) and overall survival (OS) were 5 and 20.7 months, respectively. The combination of Durvalumab and Paclitaxel is safe, leaving room for additional agents. This is the first report on the combination of Durvalumab and Paclitaxel in the treatment of TNBC (NCT02628132).


Assuntos
Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Paclitaxel/efeitos adversos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Intervalo Livre de Progressão , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/secundário , Adulto Jovem
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