RESUMO
The incidence of breast cancer is perpetually growing globally, and it remains a major public health problem and the leading cause of mortality in women. Though the aberrant activities of the Hippo pathway have been reported to be associated with cancer, constructive knowledge of the pathway connecting the various elements of breast cancer remains to be elucidated. The Hippo transducers, yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ), are reported to be either tumor suppressors, oncogenes, or independent prognostic markers in breast cancer. Thus, there is further need for an explicative evaluation of the dilemma with this molecular contribution of Hippo transducers in modulating breast malignancy. In this review, we summarize the intricate crosstalk of the Hippo pathway in different aspects of breast malignancy, including stem-likeness, cellular signaling, metabolic adaptations, tumor microenvironment, and immune responses. The collective data shows that Hippo transducers play an indispensable role in mammary tumor formation, progression, and dissemination. However, the cellular functions of YAP/TAZ in tumorigenesis might be largely dependent on the mechanical and biophysical cues they interact with, as well as on the cell phenotype. This review provides a glimpse into the plausible biological contributions of the cascade to the inward progression of breast carcinoma and suggests potential therapeutic prospects.
Assuntos
Neoplasias da Mama , Via de Sinalização Hippo , Animais , Feminino , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Microambiente Tumoral , Proteínas de Sinalização YAP/metabolismoRESUMO
Altered aerobic glycolysis is the robust mechanism to support cancer cell survival and proliferation beyond the maintenance of cellular energy metabolism. Several investigators portrayed the important role of deregulated glycolysis in different cancers, including breast cancer. Breast cancer is the most ubiquitous form of cancer and the primary cause of cancer death in women worldwide. Breast cancer with increased glycolytic flux is hampered to eradicate with current therapies and can result in tumor recurrence. In spite of the low order efficiency of ATP production, cancer cells are highly addicted to glycolysis. The glycolytic dependency of cancer cells provides potential therapeutic strategies to preferentially kill cancer cells by inhibiting glycolysis using antiglycolytic agents. The present review emphasizes the most recent research on the implication of glycolytic enzymes, including glucose transporters (GLUTs), hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase-A (LDHA), associated signalling pathways and transcription factors, as well as the antiglycolytic agents that target key glycolytic enzymes in breast cancer. The potential activity of glycolytic inhibitors impinges cancer prevalence and cellular resistance to conventional drugs even under worse physiological conditions such as hypoxia. As a single agent or in combination with other chemotherapeutic drugs, it provides the feasibility of new therapeutic modalities against a wide spectrum of human cancers.
Assuntos
Neoplasias da Mama , Glicólise , Feminino , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , Hexoquinase/antagonistas & inibidoresRESUMO
Aside from the high prevalence of incidents of breast cancer, the high grade of heterogeneity and the dearth of standard treatment guidelines make triple-negative breast cancer (TNBC) the most refractory subtype. Though still in its infancy, the Hippo pathway has been known to play a critical role in tumorigenesis. However, the molecular mechanics through which the pathway exploits the breast cancer (BC) cell vulnerability are largely unexplored. In this study, we observed a relatively higher expression of the Hippo effector, yes-associated protein (YAP), in TNBC patients compared to non-TNBC patients. Thus, we sought to investigate the contribution of Hippo signaling in TNBC by focusing particularly on transducers of the pathway. Impeding YAP transactivation by means of RNA interference or pharmacological inhibition was carried out, followed by evaluation of the subsequent biological changes at the molecular level. We successfully translated the observed data into a TNBC patient-derived xenograft cell line (PDXC). We discovered that nuclear translocation of YAP was associated with TNBC aggressive characteristics and activated the EGFR-AKT axis. Here, we explored the putative role of the Hippo transducer in enhancing cancer hostility and observed that YAP transduction drives proliferation, migration, and survival of TNBC by preventing cellular apoptosis through mediating EGFR activation. These observations suggest that YAP represents a major vulnerability in TNBC cells that may be exploited therapeutically.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias de Mama Triplo Negativas , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Proliferação de Células , Receptores ErbB/metabolismo , Xenoenxertos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Therapies targeting the PD-1/PD-L1 axis have recently been implemented for triple negative breast cancer (TNBC) management with limited efficacy, indicating that this axis may promote tumor growth by means other than immune suppression. Because PD-L1 overexpression causes resistance to the chemotherapeutic response in many cancers, here we explored the tumor promoting role of the PD-1/PD-L1 axis in breast cancer. We observed that the downregulation of PD-L1 by specific siRNA and pharmacological inhibitor significantly suppressed tumor cell proliferation, invasion and migration thereby enhancing T cell-mediated cell killing in vitro. We also showed that inhibiting PD-L1 improves cytotoxic sensitivity to chemotherapy in TNBC cells. Our in vivo results confirmed that combining a PD-L1 inhibitor with chemotherapy could significantly reduce tumor progression by inhibiting epithelial-mesenchymal transition. Overall, our results proved that PD-L1 contributes to the transformation and progression of breast cancer cells and that its intervention is a promising therapeutic strategy against breast cancer.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Antígeno B7-H1/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/genética , Transição Epitelial-Mesenquimal , Linhagem Celular TumoralRESUMO
Breast cancer is the frequently diagnosed cancer and the leading cancer death among women. The growing tumour of the breast is composed of both normoxic and hypoxic cells, and the heterogeneity of tumour affects the targeted treatment strategies against breast cancer. The functional and therapeutic status of the Warburg effect is mostly recognized, and the genes involved in glycolysis have become a target for anticancer therapeutic strategies. Glut-1 is essential for basal glucose uptake among the glucose transporters and could act as a potential target for anticancer therapy. In the present study, we explored the alteration in the metabolic phenotype of SKBR-3 cells, representing HER-2 overexpressed breast cancer cell line, with Glut-1 inhibition by a synthetic small molecule inhibitor WZB117 in the presence or absence of cobalt chloride (CoCl2) induced biochemical hypoxia in vitro. We found that WZB117 and CoCl2 in combination could inhibit metabolic phenotype characteristics such as glucose uptake, cell migration, lactate and ATP production in SKBR-3 cells. Also, Glut-1 inhibition induced apoptosis and cell cycle arrest at the G0-G1 phase even under CoCl2-induced mimic hypoxia. Our findings suggest that Glut-1 inhibition by WZB117 could overcome the protective effect of CoCl2 mimic hypoxia by regulating glycolysis and altering the metabolic phenotype of breast cancer cells. The considering excellent efficacy and minimal toxicity suggest that WZB117 may be a promising anticancer drug to the current therapies.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Hipóxia , Glicólise , Fenótipo , Glucose/metabolismoRESUMO
Antitumor immune evasion is a hallmark for the development and progression of cancer. Tumor cells adopt various mechanisms to escape the host immune system recognition. One such mechanism is the over expression of programmed death ligand (PD-L1), a negative T cell regulatory molecule. Because PD-L1 overexpression causes resistance to chemotherapeutic response in many cancers, herein we explored the relationship between PD-L1 and multidrug resistance protein MDR1 in breast cancer. Immunohistochemical evaluation of PD-L1 and MDR1 proteins in 194 breast cancer tissue samples were carried out. The relationship between PD-L1 and MDR1 expression on cancer cells with clinicopathological factors and prognosis was investigated. IHC showed a significant correlation between PD-L1 and MDR1 expression on tumor cells. Increased PD-L1 expression was also associated with lymph node status and tumor grade of the patient. Our results also revealed that the expression of PD-L1 and MDR1 was higher in TNBC subtype compared to other breast cancer subtypes. Therefore, a better understanding of the molecular mechanism through which PD-1/PD-L1 pathway contribute to the chemoresistance might bring forth the prognostic significance of PD-L1 and selection of patients who may benefit from immunotherapy.