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1.
Commun Biol ; 4(1): 72, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452400

RESUMO

Inflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cells in vitro and inhibited tumor growth and metastasis in IBC xenograft mouse models. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology.

2.
JCO Oncol Pract ; : OP2000622, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33492987

RESUMO

The clinical progression patterns of metastatic breast cancer (MBC) are heterogeneous; patients experience acute and stable phases at different time points. The acute phase consists of rapid progressive symptomatic changes, whereas in the stable phase, patients have relatively low symptom burden. Therefore, personalized interdisciplinary care is essential. The optimal palliative or supportive care in MBC is to provide comprehensive care that is individually prioritized to the patient's disease status. The purpose of this review is to provide a practical guide for oncologists to understand the priorities for supportive care for patients with MBC in the two phases. We note that for better decision making in patient care, performance status should be broadened to consider not only physical status but also psychosocial needs and cognitive condition. We summarize the clinical importance of physical symptom control, psychosocial support, physical activity, nutrition support, and advance care planning. For optimal care, we present palliative or supportive care checklists according to the disease progression phase, combining the limited evidence with expert input. In the acute phase, close monitoring of the patient's status and symptom management take priority. In the stable phase, the focus can shift to maintenance or improvement of physical strength and emotional condition. Finally, we discuss future directions and unmet needs in providing the best supportive care for patients with MBC.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33475878

RESUMO

PURPOSE: The purpose of this review is to clarify the association of body composition with breast cancer risk and treatment, including physiological mechanisms, and to elucidate strategies for overcoming unfavorable body composition changes that relate to breast cancer progression. METHODS: We have summarized updated knowledge regarding the mechanism of the negative association of altered body composition with breast cancer risk and treatment. We also review strategies for reversing unfavorable body composition based on the latest clinical trial results. RESULTS: Body composition changes in patients with breast cancer typically occur during menopause or as a result of chemotherapy or endocrine therapy. Dysfunction of visceral adipose tissue (VAT) in the setting of obesity underlies insulin resistance and chronic inflammation, which can lead to breast cancer development and progression. Insulin resistance and chronic inflammation are also observed in patients with breast cancer who have sarcopenia or sarcopenic obesity. Nutritional support and a personalized exercise program are the fundamental interventions for reversing unfavorable body composition. Other interventions that have been explored in specific situations include metformin, testosterone, emerging agents that directly target the adipocyte microenvironment, and bariatric surgery. CONCLUSIONS: A better understanding of the biology of body composition phenotypes is key to determining the best intervention program for patients with breast cancer.

4.
Bioorg Med Chem ; 32: 116013, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33482584

RESUMO

Antibody-drug conjugates (ADCs) hold great therapeutic promise for cancer indications; however, treating tumors with intratumor heterogeneity remains challenging. We hypothesized that ADCs that can simultaneously target two different cancer antigens could address this issue. Here, we report controlled production and evaluation of bispecific ADCs chemically functionalized with tumor-targeting small molecules. Enzyme-mediated conjugation of bi-functional branched linkers and following sequential orthogonal click reactions with payload and tumor targeting modules (folic acid or RGD peptide) afforded homogeneous bispecific ADCs with defined ligand/drug-to-antibody ratios ranging from 4 + 4 to 16 + 4 (ligand/payload). Most bispecific ADCs were stable under physiological conditions for 14 days. Functionalization with the cancer-specific ligands did not impair cathepsin B-mediated payload release from ADCs. Bispecific ADCs targeting the folate receptor (FR)/human epidermal growth factor receptor 2 (HER2) demonstrated specific binding and high cell killing potency only in cells expressing either antigen (FR or HER2). Integrin/HER2 bispecific ADCs equipped with RGD peptides also showed target-specific binding and cytotoxicity in integrin- or HER2-positive cells. These findings suggest that our small-molecule based bispecific ADCs have the potential to effectively treat tumors with heterogeneous antigen expression.

5.
Ann Surg Oncol ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33403525

RESUMO

INTRODUCTION: The role of modified radical mastectomy (MRM) in patients with de novo stage IV inflammatory breast cancer (IBC) remains controversial. We evaluated the impact of MRM on outcomes in this population. METHODS: Ninety-seven women presenting with stage IV IBC were identified in an institutional database (2007-2016) and were stratified by receipt of MRM or no surgery (non-MRM). Demographic, clinicopathologic, and treatment factors were compared. Local-regional recurrence patterns were described and survival analyses were conducted. RESULTS: All patients initially received chemotherapy. Fifty-two patients (53.6%) underwent MRM; 47 received post-mastectomy radiation. Differences between the non-MRM and MRM groups included tumor receptor subtypes (hormone receptor-positive [HR+]/human epidermal growth factor receptor 2-positive [HER2+]: 4.4% vs. 19.2%; HR+/HER2-negative [HER2-]: 31.1% vs. 44.2%; HR-negative [HR-]/HER2+: 24.4% vs. 15.4%; and HR-/HER2-: 40.0% vs. 21.2%; p = 0.03), number of metastatic sites (3 vs. 2; p = 0.01), and clinical partial/complete response to chemotherapy (13.3% vs. 75.0%; p < 0.001). Of the 47 patients who completed trimodality therapy, 6 (12.8%) had a local-regional recurrence. Median overall survival (OS) was 19 months in the non-MRM group and 58 months in the MRM group (p < 0.001). On multivariable analysis, clinical N3 disease (hazard ratio 2.16, 95% confidence interval [CI] 1.07-4.37; p = 0.03) as well as tumor subtypes HR+/HER2- (hazard ratio 4.98, 95% CI 1.15-21.47; p = 0.03) and HR-/HER2- (hazard ratio 7.18, 95% CI 1.66-31.07; p = 0.008) were associated with decreased OS. Partial/complete response of distant disease to chemotherapy (hazard ratio 0.43, 95% CI 0.24-0.77; p = 0.005) and receipt of MRM (hazard ratio 0.52, 95% CI 0.29-0.93; p = 0.03) were independently associated with improved OS. CONCLUSIONS: In our retrospective study, MRM in de novo stage IV IBC patients is an independent factor associated with improved OS. Our findings strongly support the need for prospective randomized trials evaluating possible survival benefits of MRM in de novo stage IV IBC patients.

6.
Cancer Res ; 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514514

RESUMO

Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ER)α-negativity. Here we explored the role of the second ER subtype, ERß, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation of ERß in IBC cells promoted cell migration and activated gene networks that control actin reorganization, including G-protein coupled receptors and downstream effectors that activate Rho GTPases. Analysis of preclinical mouse models of IBC revealed decreased metastasis of IBC tumors when ERß was expressed or activated by chemical agonists. Our findings support a tumor-suppressive role of ERß by demonstrating the ability of the receptor to inhibit dissemination of IBC cells and prevent metastasis. Based on these findings, we propose ERß as a potentially novel biomarker and therapeutic target that can inhibit IBC metastasis and reduce its associated mortality.

7.
Mol Cancer Ther ; 20(2): 296-306, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33323457

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive subgroup of breast cancer, and patients with TNBC have few therapeutic options. Apoptosis resistance is a hallmark of human cancer, and apoptosis regulators have been targeted for drug development for cancer treatment. One class of apoptosis regulators is the inhibitors of apoptosis proteins (IAPs). Dysregulated IAP expression has been reported in many cancers, including breast cancer, and has been shown to be responsible for resistance to chemotherapy. Therefore, IAPs have become attractive molecular targets for cancer treatment. Here, we first investigated the antitumor efficacy of birinapant (TL32711), a biindole-based bivalent mimetic of second mitochondria-derived activator of caspases (SMACs), in TNBC. We found that birinapant as a single agent has differential antiproliferation effects in TNBC cells. We next assessed whether birinapant has a synergistic effect with commonly used anticancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), erlotinib (EGFR inhibitor), and gemcitabine, in TNBC. Among these tested drugs, gemcitabine showed a strong synergistic effect with birinapant. Birinapant significantly enhanced the antitumor activity of gemcitabine in TNBC both in vitro and in xenograft mouse models through activation of the intrinsic apoptosis pathway via degradation of cIAP2 and XIAP, leading to apoptotic cell death. Our findings demonstrate the therapeutic potential of birinapant to enhance the antitumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.

8.
Cancers (Basel) ; 12(11)2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33114311

RESUMO

The AJCC updated its breast cancer staging system to incorporate biological factors in the "prognostic stage". We undertook this study to validate the prognostic and anatomic stages for inflammatory breast cancer (IBC). We established two cohorts of IBC diagnosed without distant metastasis: (1) patients treated at The University of Texas MD Anderson Cancer Center between 1991 and 2017 (MDA cohort) and (2) patients registered in the national Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 (SEER cohort). For prognostic staging, estrogen receptor (ER)+/progesterone receptor (PR)+/ human epidermal growth factor receptor-2 (HER2)+/grade 1-2 was staged as IIIA; ER+/PR-/HER2-/grade 3, ER-/PR+/HER2-/grade 3, and triple-negative cancers as IIIC; and all others as IIIB. Endpoints were breast cancer-specific survival (BCSS), overall survival (OS), and disease-free survival (DFS). We studied 885 patients in the MDA cohort and 338 in the SEER cohort. In the MDA cohort, the prognostic stage showed significant predictive power for BCSS, OS, and DFS (all p < 0.0001), although the anatomic stage did not. In both cohorts, the Harrell concordance index (C index) was significantly higher in the prognostic stage than the anatomic stage for all endpoints. In conclusion, the prognostic stage provided more accurate prognostication for IBC than the anatomic stage. Our results show that the prognostic staging is applicable in IBC.

9.
Mol Ther Oncolytics ; 18: 579-586, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32995482

RESUMO

Adipose stromal cells (ASCs) recruited by tumors contribute to the population of cancer-associated fibroblasts. ASCs have been reported to induce tumor growth and chemotherapy resistance. The effect of ASCs on metastasis has not been explored. Here, we investigated the role of ASCs in cancer aggressiveness and tested them as a therapy target. We show that ASCs promote the epithelial-mesenchymal transition and invasiveness of triple-negative breast cancer cells. In human cell lines derived from various types of breast tumors, ASCs suppressed cytotoxicity of cisplatin and paclitaxel. D-CAN, a proapoptotic peptide targeting ASC, suppressed spontaneous breast cancer lung metastases in a mouse allograft model when combined with cisplatin. Moreover, in a human breast cancer xenograft model, treatment with D-CAN alone was sufficient to suppress lung metastases. This study improves our understanding of how tumor stromal cells recruited from fat tissue stimulate carcinoma progression to chemotherapy resistance/metastasis and outlines a new approach to combination cancer treatment.

10.
JCO Clin Cancer Inform ; 4: 839-853, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32970482

RESUMO

PURPOSE: Unplanned health care encounters (UHEs) such as emergency room visits can occur commonly during cancer chemotherapy treatments. Patients at an increased risk of UHEs are typically identified by clinicians using performance status (PS) assessments based on a descriptive scale, such as the Eastern Cooperative Oncology Group (ECOG) scale. Such assessments can be bias prone, resulting in PS score disagreements between assessors. We therefore propose to evaluate PS using physical activity measurements (eg, energy expenditure) from wearable activity trackers. Specifically, we examined the feasibility of using a wristband (band) and a smartphone app for PS assessments. METHODS: We conducted an observational study on a cohort of patients with solid tumor receiving highly emetogenic chemotherapy. Patients were instructed to wear the band for a 60-day activity-tracking period. During clinic visits, we obtained ECOG scores assessed by physicians, coordinators, and patients themselves. UHEs occurring during the activity-tracking period plus a 90-day follow-up period were later compiled. We defined our primary outcome as the percentage of patients adherent to band-wear ≥ 80% of 10 am to 8 pm for ≥ 80% of the activity-tracking period. In an exploratory analysis, we computed hourly metabolic equivalent of task (MET) and counted 10 am to 8 pm hours with > 1.5 METs as nonsedentary physical activity hours. RESULTS: Forty-one patients completed the study (56.1% female; 61.0% age 40-60 years); 68% were adherent to band-wear. ECOG score disagreement between assessors ranged from 35.3% to 50.0%. In our exploratory analysis, lower average METs and nonsedentary hours, but not higher ECOG scores, were associated with higher 150-day UHEs. CONCLUSION: The use of a wearable activity tracker is generally feasible in a similar population of patients with cancer. A larger randomized controlled trial should be conducted to confirm the association between lower nonsedentary hours and higher UHEs.

11.
Cancers (Basel) ; 12(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32883032

RESUMO

Inflammatory breast cancer (IBC), although rare, is the most aggressive type of breast cancer. Only 2-4% of breast cancer cases are classified as IBC, but-owing to its high rate of metastasis and poor prognosis-8% to 10% of breast cancer-related mortality occur in patients with IBC. Currently, IBC-specific targeted therapies are not available, and there is a critical need for novel therapies derived via understanding novel targets. In this review, we summarize the biological functions of critical signaling pathways in the progression of IBC and the preclinical and clinical studies of targeting these pathways in IBC. We also discuss studies of crosstalk between several signaling pathways and the IBC tumor microenvironment.

12.
Breast Cancer Res Treat ; 183(3): 729-739, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32720114

RESUMO

PURPOSE: Combinations of endocrine therapy (ET) and targeted therapy (CDK4/6 or mTOR inhibitors) are standard of care for HR+/HER2- metastatic breast cancer (MBC). When ET is not effective, chemotherapy is commonly used. However, clinical outcomes of chemotherapy in the endocrine-resistant setting are limited. The purpose of this study was to identify predictive factors and the compare efficacies of chemotherapy agents in endocrine-resistant MBC. METHODS: We conducted a retrospective study of patients with HR+/HER2- MBC who received chemotherapy after progression on ET with or without targeted therapy at MD Anderson Cancer Center from 1999 to 2017. We collected baseline clinicopathological and all treatment data. Primary endpoint was time to treatment failure (TTF) of first-line chemotherapy for MBC. RESULTS: For the 1258 patients analyzed, mean age was 55.3 years (range 21-91). Previous treatment with targeted therapy was recorded for 390 patients (31%): 264 with CDK4/6 inhibitor, 205 with mTOR inhibitor, and 79 treated with both. The most frequent chemotherapy agents were capecitabine (48.9%) and taxanes (28.6%). After adjustment for all factors in a multivariate model, previous treatment with a CDK4/6 inhibitor had the strongest negative effect on TTF regardless of ET duration (hazard ratio [HR] 1.84; 95%CI 1.49-2.27; p < 0.001). Conversely, capecitabine had significantly longer median TTF than taxanes regardless of whether patients had prior exposure to taxanes in primary setting (6.1 vs 4.9 months; HR 0.64; 95%CI 0.55-0.75; p < 0.001). CONCLUSIONS: Previous exposure to CDK4/6 inhibitor had a negative predictive effect for the efficacy of chemotherapy. Capecitabine had the best efficacy against endocrine-resistant breast cancer.

13.
Ann Surg Oncol ; 27(12): 4603-4612, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32710271

RESUMO

BACKGROUND: Modified radical mastectomy (MRM), which includes axillary dissection, is the standard of care for inflammatory breast cancer (IBC). While more limited axillary staging after neoadjuvant chemotherapy (NAC) in clinically node-positive non-IBC has been increasingly adopted, the impact of these techniques in IBC is not clear. To inform patient selection for further study of limited axillary surgery, we aimed to describe the frequency and factors associated with pathological node-negativity (ypN0) in IBC. METHODS: Patients with IBC who received NAC and MRM were identified from a prospective institutional database (2004-2019). Binary logistic regression analyses were conducted to identify factors associated with ypN0. RESULTS: Of 453 patients, 189 (41.7%) had a post-NAC clinical nodal stage (ycN stage) of N0 (ycN1: 150, 33.1%; ycN2: 4, 0.9%; ycN3: 47, 10.4%; unknown: 63, 13.9%); 156 (34%) were ypN0. On multivariable analysis, higher tumor grade was not associated with ypN0 (odds ratio [OR] 1.59, 95% confidence interval [CI] 0.90-2.81, p =0.11). Compared with hormone receptor (HR)-negative/human epidermal growth factor receptor 2 (HER2)-negative tumors (n =113, 24.9%), HR-positive/HER2-negative tumors (n =169, 37.3%) had a trend toward less ypN0 (OR 0.55, 95% CI 0.29-1.02, p =0.06); HR-positive/HER2-positive tumors (n =79, 17.4%) were similar to HR-negative/HER2-negative tumors (OR 0.72, 95% CI 0.35-1.48, p =0.37); and HR-negative/HER2-positive tumors (n =92, 20.3%) were associated with increased ypN0 (OR 4.82, 95% CI 2.41-9.63, p <0.001). As ycN stage increased, the likelihood of ypN0 decreased compared with ycN0 patients (ycN1/2: OR 0.54, 95% CI 0.32-0.89, p =0.02; ycN3: OR 0.29, 95% CI 0.13-0.67, p =0.004). CONCLUSIONS: One-third of patients with IBC who received NAC and MRM had pathologically negative nodes. Factors associated with ypN0 included ycN0 status and HR-negative/HER2-positive subtype. Large, prospective studies are needed to investigate the feasibility of alternative nodal evaluation strategies in IBC, with consideration to these subgroups.

14.
JCO Clin Cancer Inform ; 4: 583-601, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32598179

RESUMO

PURPOSE: Performance status (PS) is a key factor in oncologic decision making, but conventional scales used to measure PS vary among observers. Consumer-grade biometric sensors have previously been identified as objective alternatives to the assessment of PS. Here, we investigate how one such biometric sensor can be used during a clinic visit to identify patients who are at risk for complications, particularly unexpected hospitalizations that may delay treatment or result in low physical activity. We aim to provide a novel and objective means of predicting tolerability to chemotherapy. METHODS: Thirty-eight patients across three centers in the United States who were diagnosed with a solid tumor with plans for treatment with two cycles of highly emetogenic chemotherapy were included in this single-arm, observational prospective study. A noninvasive motion-capture system quantified patient movement from chair to table and during the get-up-and-walk test. Activity levels were recorded using a wearable sensor over a 2-month period. Changes in kinematics from two motion-capture data points pre- and post-treatment were tested for correlation with unexpected hospitalizations and physical activity levels as measured by a wearable activity sensor. RESULTS: Among 38 patients (mean age, 48.3 years; 53% female), kinematic features from chair to table were the best predictors for unexpected health care encounters (area under the curve, 0.775 ± 0.029) and physical activity (area under the curve, 0.830 ± 0.080). Chair-to-table acceleration of the nonpivoting knee (t = 3.39; P = .002) was most correlated with unexpected health care encounters. Get-up-and-walk kinematics were most correlated with physical activity, particularly the right knee acceleration (t = -2.95; P = .006) and left arm angular velocity (t = -2.4; P = .025). CONCLUSION: Chair-to-table kinematics are good predictors of unexpected hospitalizations, whereas the get-up-and-walk kinematics are good predictors of low physical activity.

15.
BMC Cancer ; 20(1): 430, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32423453

RESUMO

BACKGROUND: The purpose of this study was to determine the prognostic role of hormone receptor (HR) on inflammatory breast cancer (IBC) to elucidate its aggressive biological behavior. METHODS: We evaluated the expression of estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemical staining and determined the predictive and prognostic role of HR expression on 189 patients with HR+/HER2- IBC and 677 patients with HR+/HER2- stage III non-IBC. Furthermore, we performed gene expression (GE) analyses on 137 patients with HR+/HER2- IBC and 252 patients with HR+/HER2- non-IBC to detect genes that are specifically overexpressed in IBC. RESULTS: The expression of ER% was significantly associated with longer distant disease-free survival and overall survival. However, there was no significant relationship between ER% and neoadjuvant chemotherapy outcome. In the GE study, 84 genes were identified as significantly distinguishing HR+ IBC from non-IBC. Among the top 15 canonical pathways expressed in IBC, the ERK/MAPK, PDGF, insulin receptor, and IL-7 signaling pathways were associated with the ER signaling pathway. Upregulation of the MYC gene was observed in three of these four pathways. Furthermore, HR+/HER2- IBC had significantly higher MYC amplification, and the genetic alteration was associated with poor survival outcome. CONCLUSIONS: Higher ER expression was significantly associated with improved survival in both HR+/HER2- IBC and HR+/HER2- stage III non-IBC patients. HR+/HER2- IBC had several activated pathways with MYC upregulation, and the genetic alteration was associated with poor survival outcome. The results indicate that MYC may be a key gene for understanding the biology of HR+/HER2- IBC.

16.
PLoS One ; 15(4): e0231953, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353087

RESUMO

The original algorithm that classified triple-negative breast cancer (TNBC) into six subtypes has recently been revised. The revised algorithm (TNBCtype-IM) classifies TNBC into five subtypes and a modifier based on immunological (IM) signatures. The molecular signature may differ between cancer cells in vitro and their respective tumor xenografts. We identified cell lines with concordant molecular subtypes regardless of classification algorithm or analysis of cells in vitro or in vivo, to establish a panel of clinically relevant molecularly stable TNBC models for translational research. Gene expression data were used to classify TNBC cell lines using the original and the revised algorithms. Tumor xenografts were established from 17 cell lines and subjected to gene expression profiling with the original 2188-gene algorithm TNBCtype and the revised 101-gene algorithm TNBCtype-IM. A total of six cell lines (SUM149PT (BL2), HCC1806 (BL2), SUM149PT (BL2), BT549 (M), MDA-MB-453 (LAR), and HCC2157 (BL1)) maintained their subtype classification between in vitro and tumor xenograft analyses across both algorithms. For TNBC molecular classification-guided translational research, we recommend using these TNBC cell lines with stable molecular subtypes.


Assuntos
Pesquisa Médica Translacional , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Humanos , Camundongos
17.
Sci Rep ; 10(1): 8537, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444778

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients with TNBC tumors expressing high levels of ERK2 have a poorer prognosis than those with low ERK2-expressing tumors. The MAPK pathway is often found to be highly activated in TNBC, however the precise functions of the ERK isoforms (ERK1 and ERK2) in cancer progression have not been well defined. We hypothesized that ERK2, but not ERK1, promotes the cancer stem cell (CSC) phenotype and metastasis in TNBC. Stable knockdown clones of the ERK1 and ERK2 isoforms were generated in SUM149 and BT549 TNBC cells using shRNA lentiviral vectors. ERK2 knockdown significantly inhibited anchorage-independent colony formation and mammosphere formation, indicating compromised self-renewal capacity. This effect correlated with a reduction in migration and invasion. SCID-beige mice injected via the tail vein with ERK clones were employed to determine metastatic potential. SUM149 shERK2 cells had a significantly lower lung metastatic burden than control mice or mice injected with SUM149 shERK1 cells. The Affymetrix HGU133plus2 microarray platform was employed to identify gene expression changes in ERK isoform knockdown clones. Comparison of gene expression levels between SUM149 cells with ERK2 or ERK1 knockdown revealed differential and in some cases opposite effects on mRNA expression levels. Those changes associated with ERK2 knockdown predominantly altered regulation of CSCs and metastasis. Our findings indicate that ERK2 promotes metastasis and the CSC phenotype in TNBC.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos SCID , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Células-Tronco Neoplásicas/metabolismo , Prognóstico , RNA Interferente Pequeno/genética , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Eur J Surg Oncol ; 46(9): 1588-1595, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32253074

RESUMO

INTRODUCTION: The role of surgery for breast cancer liver metastases (BCLM) remains controversial. This study aimed to analyze survival in patients treated with hepatectomy plus systemic therapy or systemic therapy alone for BCLM and to determine selection factors to guide surgical therapy. MATERIALS AND METHODS: Patients who underwent hepatectomy plus systemic therapy (n = 136) and systemic therapy alone for isolated BCLM (n = 763) were compared. Overall survival (OS) was analyzed after propensity score matching. Intrinsic subtypes were defined as: luminal A (estrogen receptor [ER]+ and/or progesterone receptor positive [PR]+, human epidermal growth factor receptor 2 [HER2]-), luminal B (ER and/or PR+, HER2+), HER2-enriched (ER and PR-, HER2+), and basal-like (ER, PR, HER2-). RESULTS: After hepatectomy, independent predictors of poor OS were number and size of liver metastases, and intrinsic subtype (hazard ratios, 1.11, 1.16, and 4.28, respectively). Median OS was 75 and 81 months among patients with luminal B and HER2-enriched subtypes, compared with 17 and 53 months among patients with basal-like and luminal A subtypes (P < .001). Median progression-free survival (PFS) was 60 months with the HER2-enriched subtype, compared with 17, 16, and 5 months with luminal A, luminal B, and basal-like subtypes, respectively (P < .001). After propensity score matching, 5-year OS rates were 56% vs. 40% in the surgery vs. systemic therapy alone groups (P = .018). CONCLUSION: Surgical resection of BCLM yielded higher OS compared with systemic therapy alone and prolonged PFS among patients with the HER2-enriched subtype. These findings support the use of surgical therapy in appropriately selected patients, based on intrinsic subtypes.

19.
Int J Mol Sci ; 21(7)2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283767

RESUMO

C-JUN N-terminal kinases (JNKs), which belong to the mitogen-activated protein kinase (MAPK) family, are evolutionarily conserved kinases that mediate cell responses to various types of extracellular stress insults. They regulate physiological processes such as embryonic development and tissue regeneration, playing roles in cell proliferation and programmed cell death. JNK signaling is also involved in tumorigenesis and progression of several types of malignancies. Recent studies have shown that JNK signaling has crucial roles in regulating the traits of cancer stem cells (CSCs). Here we describe the functions of the JNK signaling pathway in self-renewal and differentiation, which are essential features of various types of stem cells, such as embryonic, induced pluripotent, and adult tissue-specific stem cells. We also review current knowledge of JNK signaling in CSCs and discuss its role in maintaining the CSC phenotype. A better understanding of JNK signaling as an essential regulator of stemness may provide a basis for the development of regenerative medicine and new therapeutic strategies against malignant tumors.

20.
PLoS One ; 15(3): e0229903, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214335

RESUMO

BACKGROUND: Tumor cells with a mesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis and drug resistance. Circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) and CTCs reflecting a dedifferentiated CSC phenotype may not be detected using only an anti-EpCAM antibody to capture them. We used an antibody-independent CTC enrichment platform, ApoStream®, which does not rely on any antibody, including anti-EpCAM, to capture EMT- and CSC-CTCs in breast cancer patients who received neoadjuvant chemotherapy and correlated them to pathological complete response (pCR). METHODS: Blood samples from newly diagnosed breast cancer patients were prospectively collected before neoadjuvant chemotherapy (T0), after chemotherapy but before surgery (T1), and after surgery (T2) and processed using ApoStream. CTCs detected were stained with additional markers to define 3 CTC subsets with the following phenotypes: epithelial CTCs (CK+, EpCAM+ or E-cadherin+), EMT-CTCs (ß-catenin+ or vimentin+), and CSC-CTCs (CD44+ and CD24low). RESULTS: We enrolled 55 patients, 47 of which had data for analysis. EMT-CTCs were detected in 57%, 62%, and 72% and CSC-CTCs in 9%, 22%, and 19% at the T0, T1, and T2 time points, respectively. Counts of epithelial (P = 0.225) and EMT (P = 0.522) phenotypes of CTCs at T0 did not significantly predict pCR. Moreover, no correlation between CTC count change and pCR was demonstrated. CONCLUSIONS: ApoStream was successful in detecting EMT-CTCs among patients after neoadjuvant chemotherapy. However, EMT-/CSC-CTC counts did not correlate with pCR. Due to the small sample size and heterogeneity of this patient population, further study in a larger cohort of molecularly homogeneous patients is warranted.


Assuntos
Neoplasias da Mama/sangue , Caderinas/sangue , Molécula de Adesão da Célula Epitelial/sangue , Células Neoplásicas Circulantes/metabolismo , Adulto , Idoso , Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/classificação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Contagem de Células , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Vimentina/sangue
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