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1.
Bioengineered ; 13(4): 11310-11320, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35499128

RESUMEN

Chemoresistance is a major challenge for the treatment of breast cancer (BC). Previous studies showed that miR-145 level decreases in chemoresistant BC tissues. Nevertheless, the biological function of miR-145 on docetaxel resistance of BC cells remains unclear, which is what our research attempted to clarify. RT-qPCR analyzed miR-145 level, and cell viability and colony formation assays assessed the impact of miR-145 on docetaxel resistance. Molecular mechanisms of miR-145-mediated docetaxel sensitivity were examined by Luciferase reporter assay and Western Blot assessed the function of AKT3 and PI3K/AKT signaling. Our research found that miR-145 expression presented significant downregulation in docetaxel-resistant BC cells. Meanwhile, miR-145 overexpression facilitated the docetaxel sensitivity of BC cells in vivo and in vitro, while the miR-145 inhibitor decreased the sensitivity of BC cells to docetaxel. We also observed that miR-145 inhibited docetaxel resistance mainly via downregulation of the AKT3 expression and further inhibited PI3K/AKT pathway. To conclude, this research provides a novel strategy for improving chemosensitivity through the newly identified miR-145-AKT3/PI3K-AKT signaling pathway in BC.


Asunto(s)
Neoplasias de la Mama , MicroARNs , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular , Docetaxel/farmacología , Femenino , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo
2.
Biochemistry (Mosc) ; 87(Suppl 1): S86-S47, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35501988

RESUMEN

In the article, the author examines the properties of Y-box-binding protein (YB-1) and expression of the YBX-1 gene in various malignant tumors and provides the data from her own prospective study in breast cancer patients. YB-1 is a member of the highly conserved family of cold shock proteins with multiple functions in the cytoplasm and cell nucleus. YB-1 is involved in embryogenesis; it ensures cell proliferation and protects cell from the action of various aggressive environmental factors. In adult organisms, YB-1 is involved in a variety of cellular functions that regulate malignant phenotype in several types of tumors. YB-1 is a molecular marker of tumor progression that can be used in clinical practice as both prognostic factor and a target for anticancer therapy. Our prospective clinical study showed that expression of YB-1 mRNA is an independent prognostic factor, as breast cancer patients expressing YB-1 have a lower disease-free survival rate, regardless of the tumor stage and biological subtype. We recommend determining the level of YB-1 mRNA expression as a prognostic test in breast cancer patients.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Pronóstico , Estudios Prospectivos , ARN Mensajero/metabolismo , Proteína 1 de Unión a la Caja Y/genética , Proteína 1 de Unión a la Caja Y/metabolismo
3.
STAR Protoc ; 3(2): 101305, 2022 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-35496808

RESUMEN

Previously published protocols for quantification of endosomal recycling are limited by the use of radioactive reagents, washing of cells in reducing buffers, or the requirement for large numbers of cells. Here, we describe a protocol for quantification of endosomal recycling using immunofluorescence that is optimized for EGFR in BT-549 breast cancer cells but could be applied to other RTKs and cell lines. Our protocol enables quick assessment of recycling and uses a relatively small number of cells. For complete details on the use and execution of this protocol, please refer to Lonic et al. (2021).


Asunto(s)
Neoplasias de la Mama , Receptores ErbB , Neoplasias de la Mama/metabolismo , Endosomas/metabolismo , Receptores ErbB/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Coloración y Etiquetado
4.
Commun Biol ; 5(1): 403, 2022 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-35501367

RESUMEN

Estrogen receptor (ER) positive breast cancer represents 75% of all breast cancers in women. Although patients with ER+ cancers receive endocrine therapies, more than 30% develop resistance and succumb to the disease, highlighting the need to understand endocrine resistance. Here we show an unexpected role for the cell polarity protein SCRIB as a tumor-promoter and a regulator of endocrine resistance in ER-positive breast cancer cells. SCRIB expression is induced by estrogen signaling in a MYC-dependent manner. SCRIB interacts with SLC3A2, a heteromeric component of leucine amino acid transporter SLC7A5. SLC3A2 binds to the N-terminus of SCRIB to facilitate the formation of SCRIB/SLC3A2/LLGL2/SLC7A5 quaternary complex required for membrane localization of the amino acid transporter complex. Both SCRIB and SLC3A2 are required for cell proliferation and tamoxifen resistance in ER+ cells identifying a new role for the SCRIB/SLC3A2 complex in ER+ breast cancer.


Asunto(s)
Neoplasias de la Mama , Tamoxifeno , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular , Estrógenos , Femenino , Cadena Pesada de la Proteína-1 Reguladora de Fusión , Humanos , Transportador de Aminoácidos Neutros Grandes 1 , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Tamoxifeno/farmacología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
5.
BMC Womens Health ; 22(1): 145, 2022 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-35501747

RESUMEN

BACKGROUND: Preliminary clinical observations show that contemporaneous hereditary breast cancer (CHBC) patients suffered breast cancer at an early age, which requires further analysis. METHODS: 38 familial hereditary breast cancer patients (18 CHBC patients and 20 non-CHBC patients) were screened out and 152 non-hereditary breast cancer patients were used as control subjects. Clinical pathologic subtypes, age, tumor location, histological grade, lymph node metastasis, and molecular phenotype expression (ER, PR, HER-2, Ki-67, CK5/6, E-cad, P63, and P120) were compared across all subgroups. RESULTS: The incidence of CHBC was 9.47% (18/190) in breast cancer patients. The average ages of onset of CHBC patients, non-CHBC patients, and non-hereditary breast cancer patients were 49.06 ± 6.42, 60.75 ± 9.95 and 61.69 ± 14.34 respectively; whereas there were no significant differences with respect to pathological type or tumor location. There were significant differences in some histological grading (grade II/III), lymph node metastasis and PR expression between hereditary and non-hereditary breast cancers (P < 0.05; P < 0.05 and P < 0.005, respectively). Significantly different HER-2 expression was observed when comparing all hereditary or CHBC patients with non-hereditary breast cancers (P < 0.05 and P < 0.005, respectively). There were significant differences in E-cad and P63 between contemporaneous hereditary and non-hereditary breast cancers (P < 0.005 and P < 0.05, respectively). CONCLUSIONS: CHBC patients accounted for 9.47% (18/190) of breast cancer patients, had earlier disease onset, and showed differences compared to non-hereditary breast cancer patients with respect to molecular phenotype and clinical characteristics.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Incidencia , Metástasis Linfática , Fenotipo
6.
Einstein (Sao Paulo) ; 20: eGS6655, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35544899

RESUMEN

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancer cases. Ado-trastuzumab emtansine (T-DM1) is approved to treat residual HER2-positive breast cancer after neoadjuvant therapy. The aim of this study was to determine the quality-adjusted time with symptoms or toxicity and without symptoms or toxicity (Q-TWiST) of T-DM1 compared to trastuzumab for residual invasive HER2-positive breast cancer. METHODS: The authors developed an analytical model extracting individual patient data and estimated invasive disease-free survival and overall survival over a 30-year time horizon. Only direct costs from adjuvant treatment were considered as well as relapse treatment from Brazilian and American payer perspectives. Heart events were considered for utility and cost analysis. RESULTS: The 30-year projection utilizing the Weibull method estimated a mean invasive disease-free survival of 16.4 years for T-DM1 and 10.4 for Trastuzumab, in addition to a mean overall survival of 18.1 and 15.4 years, respectively. We determined a Q-TWiST gain of 3,812 years for the T-DM1 arm when compared to trastuzumab and an Incremental cost-effectiveness ratio per Q-TWiST of US$ 11,467.65 in the United States and US$ 3,332.73 in Brazil. CONCLUSION: Ado-trastuzumab emtansine is cost-effective from both Brazilian and American perspectives.


Asunto(s)
Neoplasias de la Mama , Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Análisis Costo-Beneficio , Femenino , Humanos , Terapia Neoadyuvante , Receptor ErbB-2/metabolismo , Receptor ErbB-2/uso terapéutico , Trastuzumab/uso terapéutico , Estados Unidos
7.
Oxid Med Cell Longev ; 2022: 8123120, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35528507

RESUMEN

Breast cancer is of the leading causes of cancer-related deaths and the most frequently diagnosed cancer among females worldwide. Despite advancements in breast cancer therapy, the disease eventually progresses in most patients because of de novo or secondary resistance. Thus, discovering novel drugs with high effectiveness and low toxicity for systemic therapy is essential. In this study, we investigated whether a new oleanolic derivative N-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-methylene-3-oxo-olean-12-en-28-amide (ZQL-4c) exhibits potential anticancer effects against breast cancer. We determined that ZQL-4c strongly inhibited cell proliferation and invasion and induced G2/M phase arrest and apoptosis in breast cancer cells. We then found that ZQL-4c induced the production of reactive oxygen species (ROS). We then found that ZQL-4c significantly inhibited Notch-AKT signaling pathways that are related to oxidative stress. Taken together, this study is the first to show that ZQL-4c can significantly suppress the growth and invasion of breast cancer by blocking Notch-Akt signaling pathways, which are mainly regulated by ROS-mediated oxidative stress. Thus, ZQL-4c might be considered a novel and potential anticancer drug for breast cancer treatment.


Asunto(s)
Neoplasias de la Mama , Proteínas Proto-Oncogénicas c-akt , Amidas/uso terapéutico , Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Masculino , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal
8.
BMC Cancer ; 22(1): 526, 2022 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-35545761

RESUMEN

BACKGROUND: A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated. METHODS: Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours. RESULTS: We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct. CONCLUSION: Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.


Asunto(s)
Neoplasias de la Mama , Biomarcadores/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proteínas Cromosómicas no Histona , Femenino , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribosomas/genética , Ribosomas/metabolismo
9.
Clin Transl Med ; 12(5): e825, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35522895

RESUMEN

AIMS: MORC family CW-type zinc finger 2 (MORC2), a GHKL-type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented. METHODS AND RESULTS: We report that MORC2 is a relatively stable protein, and the N-terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real-time PCR. The N-terminal but not C-terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N-terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone-mediated autophagy pathway. Consequently, HSP90 inhibitor 17-AAG effectively blocks the growth and metastatic potential of MORC2-expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition. CONCLUSION: We uncover a previously unknown role for HSP90 N-terminal inhibitors in promoting MORC2 degradation in a HSP90-indepentent manner and support the potential application of these inhibitors for treating MORC2-overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small-molecule inhibitors of MORC2 for anticancer therapeutic application.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Adenosina Trifosfatasas/genética , Antineoplásicos/farmacología , Autofagia/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Proteínas Oncogénicas , Factores de Transcripción
10.
J Nanobiotechnology ; 20(1): 212, 2022 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-35524270

RESUMEN

A multifunctional nanoplatform with core-shell structure was constructed in one-pot for the synergistic photothermal, photodynamic, and chemotherapy against breast cancer. In the presence of gambogic acid (GA) as the heat-shock protein 90 (HSP90) inhibitor and the gold nanostars (AuNS) as the photothermal reagent, the assembly of Zr4+ with tetrakis (4-carboxyphenyl) porphyrin (TCPP) gave rise to the nanocomposite AuNS@ZrTCPP-GA (AZG), which in turn, further coated with PEGylated liposome (LP) to enhance the stability and biocompatibility, and consequently the antitumor effect of the particle. Upon cellular uptake, the nanoscale metal - organic framework (NMOF) of ZrTCPP in the resulted AuNS@ZrTCPP-GA@LP (AZGL) could be slowly degraded in the weak acidic tumor microenvironment to release AuNS, Zr4+, TCPP, and GA to exert the synergistic treatment of tumors via the combination of AuNS-mediated mild photothermal therapy (PTT) and TCPP-mediated photodynamic therapy (PDT). The introduction of GA serves to reduce the thermal resistance of the cell to re-sensitize PTT and the constructed nanoplatform demonstrated remarkable anti-tumor activity in vitro and in vivo. Our work highlights a facile strategy to prepare a pH-dissociable nanoplatform for the effective synergistic treatment of breast cancer.


Asunto(s)
Neoplasias de la Mama , Estructuras Metalorgánicas , Nanocompuestos , Fotoquimioterapia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Liposomas/uso terapéutico , Microambiente Tumoral , Xantonas
11.
Iran J Allergy Asthma Immunol ; 21(1): 12-19, 2022 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-35524373

RESUMEN

MicroRNA-155 (miR-155) has a critical role in pro-inflammatory activation and tumor progression. In addition, miR-155 has various oncogenic effects in the tumor microenvironment by targeting the suppressor gene of cytokine signaling-1(SOCS-1) and interleukin-6 (IL-6). This study investigated the association of inflammatory changes with the variations of miR-155 expression in newly diagnosed breast cancer (NDBC) patients. Seventy NDBC patients were categorized as lobular and ductal subgroups and forty healthy individuals participated in this study. The expression rate of miR-155 and its downstream target gene, SOCS-1, as well as the plasma levels of IL-6, were evaluated in peripheral blood mononuclear cells of NDBC patients; using real-time PCR and enzyme-linked immunosorbent assay, respectively. Our results indicated an over-expression of miR-155 in the PBMCs of NDBC patients which was significantly associated with the tumor grade and the type of ductal carcinoma. In contrast, a significant downregulation of SOCS-1 was observed in NDBC patients compared to control group, however, there was no significant difference between two subtypes of BC. Furthermore, a higher concentration of plasma IL-6 was detected in NDBC patients compared to the healthy control group which had an inverse correlation with the SOCS-1 levels. According to the potential effects of miR-155 on regulating the expression of SOCS-1 and IL-6, we suggest this small transcript as a promising diagnostic marker for various types of BC patients.


Asunto(s)
Neoplasias de la Mama , MicroARNs , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Interleucina-6 , Leucocitos Mononucleares/metabolismo , MicroARNs/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Microambiente Tumoral
12.
Methods Enzymol ; 667: 633-662, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35525557

RESUMEN

Obtaining high-resolution structures of Receptor Tyrosine Kinases that visualize extracellular, transmembrane and intracellular kinase regions simultaneously is an eagerly pursued but still unmet challenge of structural biology. The Human Epidermal Growth Factor Receptor 3 (HER3) that has a catalytically inactive kinase domain (pseudokinase) forms a potent signaling complex upon binding of growth factor neuregulin 1ß (NRG1ß) and upon dimerization with a close homolog, the HER2 receptor. The HER2/HER3/NRG1ß complex is often referred to as an oncogenic driver in breast cancer and is an attractive target for anti-cancer therapies. After overcoming significant hurdles in isolating sufficient amounts of the HER2/HER3/NRG1ß complex for structural studies by cryo-electron microscopy (cryo-EM), we recently obtained the first high-resolution structures of the extracellular portion of this complex. Here we describe a step-by-step protocol for obtaining a stable and homogenous HER2/HER3/NRG1ß complex for structural studies and our recommendation for collecting and processing cryo-EM data for this sample. We also show improved EM density for the transmembrane and kinase domains of the receptors, which continue to evade structural determination at high resolution. The discussed strategies are tunable and applicable to other membrane receptor complexes.


Asunto(s)
Neoplasias de la Mama , Receptor ErbB-3 , Neoplasias de la Mama/metabolismo , Microscopía por Crioelectrón , Femenino , Humanos , Ligandos , Receptor ErbB-2/química , Receptor ErbB-2/metabolismo , Receptor ErbB-3/química , Receptor ErbB-3/metabolismo
13.
Cell Commun Signal ; 20(1): 45, 2022 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-35392925

RESUMEN

BACKGROUND: Breast cancer is the most common cancer in women worldwide. More than 70% of breast cancers are estrogen receptor (ER) alpha positive. Compared with ER alpha-negative breast cancer, which is more aggressive and has a shorter survival time, ER alpha-positive breast cancer could benefit from endocrine therapy. Selective estrogen receptor modulators, such as tamoxifen, are widely used in endocrine therapy. Approximately half of ER alpha-positive breast cancer patients will eventually develop endocrine resistance, making it a major clinical challenge in therapy. Thus, decoding the throughput of estrogen signaling, including the control of ER alpha expression and stability, is critical for the improvement of breast cancer therapeutics. METHODS: TRIM3 and ER alpha protein expression levels were measured by western blotting, while the mRNA levels of ER alpha target genes were measured by RT-PCR. A CCK-8 assay was used to measure cell viability. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling activity was accomplished with luciferase assays, RT-PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect ER alpha protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the ER alpha protein. RESULTS: In our current study, we found that TRIM3, an E3 ligase, can promote ER alpha signaling activity and breast cancer progression. TRIM3 depletion inhibits breast cancer cell proliferation and migration, while unbiased RNA sequencing data indicated that TRIM3 is required for the activity of estrogen signaling on the -genome-wide scale. The immunoprecipitation assays indicated that TRIM3 associates with ER alpha and promotes its stability, possibly by inducing K63-linked polyubiquitination of ER alpha. In conclusion, our data implicate a nongenomic mechanism by which TRIM3 stabilizes the ER alpha protein to control ER alpha target gene expression linked to breast cancer progression. CONCLUSION: Our study provides a novel posttranslational mechanism in estrogen signaling. Modulation of TRIM3 expression or function could be an interesting approach for breast cancer treatment. Video abstract.


Asunto(s)
Neoplasias de la Mama , Proteínas Portadoras , Neoplasias de la Mama/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Proliferación Celular , Estrógenos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Tamoxifeno/farmacología , Ubiquitina/metabolismo
14.
Oncol Rep ; 47(6)2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35445730

RESUMEN

Tamoxifen resistance remains a major obstacle in the treatment of estrogen receptor (ER)­positive breast cancer. In recent years, the crucial role of the epithelial­mesenchymal transition (EMT) process in the development of drug resistance in breast cancer has been underlined. However, the central molecules inducing the EMT process during the development of tamoxifen resistance remain to be elucidated. In the present study, it was demonstrated that tamoxifen­resistant breast cancer cells underwent EMT and exhibited an enhanced cell motility and invasive behavior. The inhibition of snail family transcriptional repressor 1 (Snail) and twist family BHLH transcription factor 1 (Twist) reversed the EMT phenotype and decreased the tamoxifen resistance, migration and invasion of tamoxifen­resistant breast cancer cells. In addition, it was observed that the inhibition of epidermal growth factor receptor (EGFR) reversed the EMT phenotype in tamoxifen­resistant MCF7 (MCF­7/TR) cells via the downregulation of Snail and Twist. Notably, the EGFR inhibitor, gefitinib, decreased tamoxifen resistance, migration and invasion through the inhibition of Snail and Twist. On the whole, the results of the present study suggest that EGFR may be a promising therapeutic target for tamoxifen­resistant breast cancer. Moreover, it was suggested that gefitinib may serve as a potent novel therapeutic strategy for breast cancer patients, who have developed tamoxifen resistance.


Asunto(s)
Neoplasias de la Mama , Tamoxifeno , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Gefitinib/uso terapéutico , Humanos , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico
15.
Int J Biol Sci ; 18(6): 2452-2471, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35414770

RESUMEN

Angiotensin II type 1 receptor-associated protein (ATRAP) is widely expressed in different tissues and organs, although its mechanistic role in breast cancer remains unclear. Here, we show that ATRAP is highly expressed in breast cancer tissues. Its aberrant upregulation promotes breast cancer aggressiveness and is positively correlated with poor prognosis. Functional assays revealed that ATRAP participates in promoting cell growth, metastasis, and aerobic glycolysis, while microarray analysis showed that ATRAP can activate the AKT/mTOR signaling pathway in cancer progression. In addition, ATRAP was revealed to direct Ubiquitin-specific protease 14 (USP14)-mediated deubiquitination and stabilization of Pre-B cell leukemia homeobox 3 (PBX3). Importantly, ATRAP is a direct target of Upstream stimulatory factor 1 (USF1), and that ATRAP overexpression reverses the inhibitory effects of USF1 knockdown. Our study demonstrates the broad contribution of the USF1/ATRAP/PBX3 axis to breast cancer progression and provides a strong potential therapeutic target.


Asunto(s)
Neoplasias de la Mama , Proteínas Proto-Oncogénicas c-akt , Proteínas Adaptadoras Transductoras de Señales , Neoplasias de la Mama/metabolismo , Femenino , Glucólisis/genética , Proteínas de Homeodominio , Humanos , Fenotipo , Proteínas Proto-Oncogénicas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitina Tiolesterasa/genética , Factores Estimuladores hacia 5'/genética , Factores Estimuladores hacia 5'/metabolismo , Factores Estimuladores hacia 5'/farmacología
16.
Int J Mol Sci ; 23(7)2022 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-35409352

RESUMEN

Extracellular vesicles (EVs) shuttle proteins, RNA, DNA, and lipids crucial for cell-to-cell communication. Recent findings have highlighted that EVs, by virtue of their cargo, may also contribute to breast cancer (BC) growth and metastatic dissemination. Indeed, EVs are gaining great interest as non-invasive cancer biomarkers. However, little is known about the biological and physical properties of EVs from malignant BC lesions, and even less is understood about EVs from non-malignant lesions, such as breast fibroadenoma (FAD), which are clinically managed using conservative approaches. Thus, for this pilot study, we attempted to purify and explore the proteomic profiles of EVs from benign breast lesions, HER2+ BCs, triple-negative BCs (TNBCs), and continuous BC cell lines (i.e., BT-549, MCF-10A, and MDA-MB-231), combining experimental and semi-quantitative approaches. Of note, proteome-wide analyses showed 49 common proteins across EVs harvested from FAD, HER2+ BCs, TNBCs, and model BC lines. This is the first feasibility study evaluating the physicochemical composition and proteome of EVs from benign breast cells and primary and immortalized BC cells. Our preliminary results hold promise for possible implications in precision medicine for BC.


Asunto(s)
Neoplasias de la Mama , Vesículas Extracelulares , Fibroadenoma , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Vesículas Extracelulares/metabolismo , Femenino , Fibroadenoma/metabolismo , Fibroadenoma/patología , Flavina-Adenina Dinucleótido/metabolismo , Humanos , Proyectos Piloto , Proteoma/metabolismo , Proteómica/métodos
17.
Bioengineered ; 13(4): 10072-10087, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35473571

RESUMEN

The incidence rate of breast cancer is the highest in the world, and major problem in the clinical treatment is the therapy resistance of breast cancer stem cells (CSCs). Thus, new therapeutic approaches targeting breast CSCs are needed. Our previous study demonstrated cancer-derived sialylated IgG (SIA-IgG) is highly expressed in cancer cells with stem/progenitor features. Furthermore, a high frequency of SIA-IgG in breast cancer tissue predicted metastasis and correlated with poor prognosis factors, and depletion of IgG in breast cancer leads to lower malignancy of cancer cells, suggesting SIA-IgG could be a potential therapeutic target in breast cancer. In this study, we first investigated the relationship of SIA-IgG expression with the clinicopathological characteristics and clinical prognosis of breast carcinoma patients, and the data confirmed that the expression of SIA-IgG confers poor prognosis in breast cancer. Successively, by using a monoclonal antibody specifically against SIA-IgG, we targeted SIA-IgG on the surface of MDA-MB-231 cells and detected their functional changes, and the results suggested SIA-IgG to be a promising antibody therapeutic target in breast cancer. In addition, we explored the mechanism of action at the molecular level of SIA-IgG on breast cancer cell, the findings suggest that SIA-IgG promotes proliferation, metastasis, and invasion of breast cancer cells through the Wnt/ß-catenin signaling pathway. Developing therapeutic antibody needs effective therapeutic target, and the antibody should better be a monoclonal antibody with high affinity and high specificity. This study provides a potential prognostic marker and a novel therapeutic target for breast cancer.


Asunto(s)
Neoplasias de la Mama , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Inmunoglobulina G , Pronóstico , Vía de Señalización Wnt
18.
Int J Pharm ; 619: 121710, 2022 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-35367334

RESUMEN

The biological synthesis of nanoparticles is a growing research trend because it has numerous pharmaceutical and biomedical applications. The present study describes the preparation, characterization and anti-cancer evaluation of silver nanoparticles synthesized using an aqueous extract of Bergenia ligulata whole plant as a reducing agent. The physiochemical properties of the Bergenia ligulata silver nanoparticles (BgAgNPs) were measured by ultraviolet-visible spectrophotometry, Fourier transform infrared spectrophotmetry (FTIR), X-ray powder diffraction (XRD) and Scanning electron microscopy (SEM) analysis for identifying functional groups, crystallinity, structural and morphological features, respectively. Further, BgAgNps, along with the Bergenia ligulata aqueous extract (BgAE), were investigated for their effects on cell proliferation and apoptosis through MTT, colony-forming assay, wound-healing assay and flow cytometry-based approaches. The cytotoxic effects were more pronounced in cells treated with BgAgNps in comparison to BgAE. These effects were evidenced by the decreasing cell viability, migration capacity and loss of characteristic morphological features. In addition, BgAgNps unveiled significant induction of apoptosis in human breast cancer (MCF-7) cells, possibly through oxidative stress-mediated reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP). Moreover, molecular mechanism-based studies revealed that BgAgNps robustly augmented p53 levels and pro-apoptotic downstream targets of p53 like Bax and cleaved caspase 3 in MCF-7 cells. Of note, BgAgNps had little or no cytotoxic effect on p53-deficient cancer cells (Mda-mb-231 and SW-620). These findings confirm that the BgAgNPs exhibited superior anti-cancer potential and could be exploited as a promising, cost-effective, and environmentally benign strategy in treating this disease in the future.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Nanopartículas del Metal , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Puntos de Control del Ciclo Celular , Femenino , Humanos , Células MCF-7 , Nanopartículas del Metal/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plata/química , Proteína p53 Supresora de Tumor
19.
Neoplasia ; 28: 100792, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35367789

RESUMEN

PURPOSE: As a promotor of tumor invasion and tumor microenvironment (TME) formation, the protein complex S100A8/S100A9 is associated with poor prognosis. Our aim was to further evaluate its origin and regulatory effects, and to establish an imaging biomarker for TME activity. METHODS: S100A9-/-cells (ko) were created from syngeneic murine breast cancer 4T1 (high malignancy) and 67NR (low malignancy) wildtype (wt) cell lines and implanted into either female BALB/c wildtype or S100A9-/- mice (n = 10 each). Anti-S100A9-Cy5.5-targeted fluorescence reflectance imaging was performed at 0 h and 24 h after injection. Potential early changes of S100A9-presence under immune checkpoint inhibition (anti-PD-L1, n = 7 vs. rat IgG2b as isotype control, n = 3) were evaluated. RESULTS: In S100A9-/-mice contrast-to-noise-ratios were significantly reduced for wt and S100A9-/-tumors. No significant differences were detected for 4T1 ko and 67NR ko cells as compared to wildtype cells. Under anti-PD-L1 treatment S100A9 presence significantly decreased compared with the control group. CONCLUSION: Our results confirm a secretion of S100A8/S100A9 by the TME, while tumor cells do not apparently release the protein. Under immune checkpoint inhibition S100A9-imaging reports an early decrease of TME activity. Therefore, S100A9-specific imaging may serve as an imaging biomarker for TME formation and activity.


Asunto(s)
Neoplasias de la Mama , Inhibidores de Puntos de Control Inmunológico , Animales , Biomarcadores , Neoplasias de la Mama/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Femenino , Humanos , Ratones , Ratas , Microambiente Tumoral
20.
Development ; 149(8)2022 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-35420674

RESUMEN

Post-lactational mammary gland regression encompasses extensive programmed cell death and removal of milk-producing epithelial cells, breakdown of extracellular matrix components and redifferentiation of stromal adipocytes. This highly regulated involution process is associated with a transient increased risk of breast cancer in women. Using a syngeneic tumour model, we show that tumour growth is significantly altered depending on the stage of involution at which tumour cells are implanted. Tumour cells injected at day 3 involution grew faster than those in nulliparous mice, whereas tumours initiated at day 6 involution grew significantly slower. These differences in tumour progression correlate with distinct changes in innate immune cells, in particular among F4/80-expressing macrophages and among TCRδ+ unconventional T cells. Breast cancer post-pregnancy risk is exacerbated in older first-time mothers and, in our model, initial tumour growth is moderately faster in aged mice compared with young mice. Our results have implications for breast cancer risk and the use of anti-inflammatory therapeutics for postpartum breast cancers.


Asunto(s)
Neoplasias de la Mama , Glándulas Mamarias Humanas , Anciano , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Lactancia , Glándulas Mamarias Animales , Ratones , Periodo Posparto/fisiología , Embarazo
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