BRCA1 tumours correlate with a HIF-1α phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression

BACKGROUND: There are limited data regarding the hypoxia pathway in familial breast cancers. We therefore performed a study of hypoxic factors in BRCA1, BRCA2 and BRCAX breast cancers. METHODS: Immunoperoxidase staining for HIF-1alpha, PHD1, PHD2, PHD3, VEGF and FIH was carried out in 125 (38 BRCA1, 33 BRCA2 and 54 BRCAX) breast carcinomas. These were correlated with clinicopathological parameters and the intrinsic breast cancer phenotypes. RESULTS: BRCA1 tumours correlated with positivity for HIF-1alpha (P=0.008) and negativity for PHD3 (P=0.037). HIF-1alpha positivity (P=0.001), PHD3 negativity (P=0.037) and nuclear FIH negativity (P=0.011) was associated with basal phenotype. HIF-1alpha expression correlated with high tumour grade (P=0.009), negative oestrogen receptor (ER) status (P=0.001) and the absence of lymph node metastasis (P=0.028). Nuclear FIH expression and PHD3 correlated with positive ER expression (P=0.024 and P=0.035, respectively). BRCA1 cancers with positive HIF-1alpha or cytoplasmic FIH had a significantly shorter relapse-free survival (P=0.007 and P=0.049, respectively). CONCLUSIONS: The aggressive nature of BRCA1 and basal-type tumours may be partly explained by an enhanced hypoxic drive and hypoxia driven ER degradation because of suppressed PHD and aberrantly located FIH expression. This may have important implications, as these tumours may respond to compounds directed against HIF-1alpha or its downstream targets

Expression of the forkhead box transcription factor FOXP1 is associated with oestrogen receptor alpha, oestrogen receptor beta and improved survival in familial breast cancers.

BACKGROUND: The role of FOXP1 in sporadic breast cancers has been widely studied but its role in familial breast cancers is yet unexplored. AIMS: To investigate FOXP1 expression in different molecular subtypes of familial breast cancers and to correlate its expression with clinicopathological parameters, oestrogen receptors (ER) and survival. METHODS: Immunohistochemical staining for FOXP1 was performed in 126 familial breast carcinomas comprising 35 BRCA1, 34 BRCA2 and 57 BRCAX. RESULTS: Nuclear FOXP1 expression ranged from focal weak to widespread strong expression. Expression of FOXP1 was higher in familial breast cancers (54%) compared with sporadic cancers (46%) (p<0.001). There was a significant correlation between FOXP1 with ERalpha (p = 0.038) and ERbeta (p = 0.007) in familial breast cancers. FOXP1 was more highly expressed in familial breast cancers compared with sporadic cancers for luminal (p = 0.021) and basal (p<0.001), but not HER2 and null phenotypes (both p>0.05). The absence of FOXP1 expression was associated with a shorter relapse-free (p = 0.025) and overall survival (p = 0.009) in familial breast cancer. Negativity for FOXP1 was associated with a significantly worse overall survival in BRCA2 cancers (p = 0.021) and there was a non-significant separation of the survival curves for BRCA1 cancers (p = 0.183). No differences in survival were seen for BRCAX cancers (p = 0.762). CONCLUSION: Results suggest that FOXP1 demonstrates different expression patterns in familial breast cancers than sporadic tumours, even in tumours showing similar phenotypes. They also suggest a different role of FOXP1 as a tumour suppressor in familial tumours, which is unrelated to ER expression and may impact on therapeutic options

Prognostic value of decreased FOXP1 protein expression in various tumors: a systematic review and meta-analysis

The prognostic value of forkhead box protein P1 (FOXP1) protein expression in tumors remains controversial. Therefore, we conducted a systematic review and meta-analysis, searching the PubMed, Embase and Web of Science databases to identify eligible studies. In total, we analyzed 22 articles that examined 9 tumor types and included 2468 patients. Overall, decreased expression of FOXP1 protein was associated with favorable overall survival (OS) in lymphoma patients (HR = 0.38, 95%CI: 0.30–0.48, p < 0.001). In patients with solid tumors, decreased FOXP1 expression correlated with unfavorable OS (HR = 1.82, 95%CI: 1.18–2.83, p = 0.007). However, when FOXP1 protein expression was nuclear, decreased expression was also associated with favorable OS (HR = 0.53, 95%CI: 0.32–0.86, p = 0.011). Furthermore, decreased FOXP1 expression resulted in the best OS in patients with mucosa-associated lymphoid tissue (MALT) lymphomas (HR = 0.26, 95%CI: 0.11–0.59, p = 0.001), but the worst OS was observed in non-small cell lung cancer (NSCLC) patients (HR = 3.11, 95%CI: 1.87–5.17, p < 0.001). In addition, decreased FOXP1 expression was significantly correlated with an unfavorable relapse-free survival (RFS) in breast cancer patients (HR = 1.93, 95%CI: 1.33–2.80, p = 0.001)

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes