RESUMO
Human papillomavirus-negative (HPV-neg) oropharyngeal squamous cell carcinomas (OPSCCs) are associated with poorer overall survival (OS) compared with HPV-positive (HPV-pos) OPSCCs. The major obstacle in improving outcomes of HPV-neg patients is the lack of robust biomarkers and therapeutic targets. Herein, we investigated the role of centrosome amplification (CA) as a prognostic biomarker in HPV-neg OPSCCs. A quantitative evaluation of CA in clinical specimens of OPSCC revealed that (a) HPV-neg OPSCCs exhibit higher CA compared with HPV-pos OPSCCs, and (b) CA was associated with poor OS, even after adjusting for potentially confounding clinicopathologic variables. Contrastingly, CA was higher in HPV-pos cultured cell lines compared to HPV-neg ones. This divergence in CA phenotypes between clinical specimens and cultured cells can therefore be attributed to an inaccurate recapitulation of the in vivo tumor microenvironment in the cultured cell lines, namely a hypoxic environment. The exposure of HPV-neg OPSCC cultured cells to hypoxia or stabilizing HIF-1α genetically increased CA. Both the 26-gene hypoxia signature as well as the overexpression of HIF-1α positively correlated with increased CA in HPV-neg OPSCCs. In addition, we showed that HIF-1α upregulation is associated with the downregulation of miR-34a, increase in CA and expression of cyclin- D1. Our findings demonstrate that the evaluation of CA may aid in therapeutic decision-making, and CA can serve as a promising therapeutic target for HPV-neg OPSCC patients.
RESUMO
Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) have been investigated as triple-negative breast cancer (TNBC) biomarkers. Reduced EGFR levels can be compensated by increases in HER3; thus, assaying EGFR and HER3 together may improve prognostic value. In a multi-institutional cohort of 510 TNBC patients, we analyzed the impact of HER3, EGFR, or combined HER3-EGFR protein expression in pre-treatment samples on breast cancer-specific and distant metastasis-free survival (BCSS and DMFS, respectively). A subset of 60 TNBC samples were RNA-sequenced using massive parallel sequencing. The combined HER3-EGFR score outperformed individual HER3 and EGFR scores, with high HER3-EGFR score independently predicting worse BCSS (Hazard Ratio [HR] = 2.30, p = 0.006) and DMFS (HR = 1.78, p = 0.041, respectively). TNBCs with high HER3-EGFR scores exhibited significantly suppressed ATM signaling and differential expression of a network predicted to be controlled by low TXN activity, resulting in activation of EGFR, PARP1, and caspases and inhibition of p53 and NFκB. Nuclear PARP1 protein levels were higher in HER3-EGFR-high TNBCs based on immunohistochemistry (p = 0.036). Assessing HER3 and EGFR protein expression in combination may identify which adjuvant chemotherapy-treated TNBC patients have a higher risk of treatment resistance and may benefit from a dual HER3-EGFR inhibitor and a PARP1 inhibitor.
Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Receptor ErbB-3/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/metabolismo , Estadiamento de Neoplasias , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Prognóstico , Receptor ErbB-3/metabolismo , Análise de Sobrevida , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Nuclear KIFC1 (nKIFC1) predicts worse outcomes in breast cancer, but its prognostic value within racially distinct triple-negative breast cancer (TNBC) patients is unknown. Thus, nKIFC1 expression was assessed by immunohistochemistry in 163 African American (AA) and 144 White TNBC tissue microarrays (TMAs) pooled from four hospitals. nKIFC1 correlated significantly with Ki67 in White TNBCs but not in AA TNBCs, suggesting that nKIFC1 is not merely a surrogate for proliferation in AA TNBCs. High nKIFC1 weighted index (WI) was associated with significantly worse overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) (Hazard Ratios [HRs] = 3.5, 3.1, and 3.8, respectively; P = 0.01, 0.009, and 0.007, respectively) in multivariable Cox models in AA TNBCs but not White TNBCs. Furthermore, KIFC1 knockdown more severely impaired migration in AA TNBC cells than White TNBC cells. Collectively, these data suggest that nKIFC1 WI an independent biomarker of poor prognosis in AA TNBC patients, potentially due to the necessity of KIFC1 for migration in AA TNBC cells.
