An overview on liposarcoma subtypes: Genetic alterations and recent advances in therapeutic strategies.

Liposarcoma (LPS) is a rare malignancy of adipocytic differentiation. According to World Health Organization classification, LPS comprises of four principle subtypes Atypical lipomatous tumor/Well-differentiated liposarcoma (ATL/WDLPS), Dedifferentiated liposarcoma (WDLPS), Myxoid liposarcoma (MLPS), and Pleomorphic liposarcoma (PLPS). Each subtype can develop at any location and shows distinct clinical behavior and treatment sensitivity. ATL/ WDLPS subtype has a higher incidence rate, low recurrence, and is insensitive to radiation and chemotherapy. DDLPS is the focal progression of WDLPS, which is aggressive and highly metastasizing. MLPS is sensitive to radiation and chemotherapy, with a higher recurrence rate and metastasis. PLPS subtype is highly metastasizing, has a poor prognosis, and exhibiting higher recurrence rate. Initial histological analysis provides information for the characterization of LPS subtypes', further molecular and genetic analysis provides certain subtype specifications, such as gene amplifications and gene fusions. Such molecular genetic alterations will be useful as therapeutic targets in various cancers, including the LPS subtypes. A wide range of novel therapeutic agents based on genetic alterations that aim to target LPS subtypes specifically are under investigation. This review summarizes the LPS subtype classification, their molecular genetic characteristics, and the implications of genetic alterations in therapeutics.

The molecular crosstalk of the hippo cascade in breast cancer: A potential central susceptibility.

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.

The determinants of metabolic discrepancies in aerobic glycolysis: Providing potential targets for breast cancer treatment.

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.

YAP transduction drives triple-negative breast cancer aggressiveness through modulating the EGFR‒AKT axis in patient-derived xenograft cells.

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.

PD-1/PD-L1 blockade inhibits epithelial-mesenchymal transition and improves chemotherapeutic response in breast cancer.

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.

Metabolic Phenotype Intricacies on Altered Glucose Metabolism of Breast Cancer Cells upon Glut-1 Inhibition and Mimic Hypoxia In Vitro.

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.

Immunohistochemical expression of PD-L1 and MDR1 in breast tumors: association with clinico-pathological parameters and treatment outcome.

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.

Histone chaperone HIRA dictate proliferation vs differentiation of chronic myeloid leukemia cells.

Abnormal proliferation and disrupted differentiation of hematopoietic progenitors mark leukemia. Histone cell cycle regulator A (HIRA), a histone chaperone, regulates hemogenic to hematopoietic transition involved in normal hematopoiesis. But, its role remains unexplored in leukemia, a case of dysregulated hematopoiesis. Here, the Cancer Cell Line Encyclopedia database analysis showed enhanced HIRA mRNA expression in cells of hematopoietic and lymphoid origin with maximal expression in the chronic myeloid leukemia (CML) cell line, K562. This observation was further endorsed by the induced expression of HIRA in CML patient samples compared to healthy individuals and Acute Myeloid Leukemia patients. Downregulation of HIRA in K562 cells displayed cell cycle arrest, loss in proliferation, presence of polyploidy with significant increase in CD41+ population thereby limiting proliferation but inducing differentiation of leukemia cells to megakaryocyte fate. Induced megakaryocyte differentiation of mouse Hira-knockout hematopoietic progenitors in vivo further confirmed the in vitro findings in leukemia cells. Molecular analysis showed the involvement of MKL1/GATA2/H3.3 axis in dictating differentiation of CML cells to megakaryocytes. Thus, HIRA could be exploited for differentiation induction therapy in CML and in chronic pathological conditions involving low platelet counts.

Role of human papilloma virus in oral tongue squamous cell carcinoma.

BACKGROUND: Human papilloma virus (HPV) is an important risk factor for head and neck cancer, specifically oropharyngeal cancer, but its association with oral tongue squamous cell carcinoma (SCC) is uncertain. The objectives were to determine the HPV16 prevalence in oral tongue SCCs, its integration status and to correlate the expression of oncogenic proteins with targets. METHODS: In this case-control study with oral tongue SCC cases (n=60) and normal oral mucosa (n=46), HPV positivity was determined by polymerase chain reaction (PCR) using consensus and HPV 16 type specific primers and p16 immunohistochemistry (IHC). The viral integration status was determined with primers specific to the E2 gene and in situ hybridization (ISH). Immunohistochemical analysis of HPV oncogenic proteins (E6, E7) and their target proteins (p53, pRb, cyclinD1, p16, Notch-1, EGFR) proteins was carried out in HPV positive cases. The data was analyzed with SPSS software (v 11.0). Survival analysis was carried out by the Kaplan-Meier method. RESULTS: HPV16 was detected in 48% (n=29) of the cases and none of the controls by PCR assay (p<0.001) while p16 IHC, as a surrogate HPV marker, detected 33% (n=18) of the cases; 18% (n=10) were detected by both the methods. Integration was observed in 83% (n=24) by E2-PCR and 67% (n=18) by ISH. The E6-p53 pathway was active in 33% of the cases; E7-pRb in 52% and both in 11%. HPV positivity was associated with well-differentiated cancers (p=0.041) and low recurrence rate (p=0.014). CONCLUSION: Our study confirms a positive correlation of HPV infection with oral tongue cancer.