Impact of FOXA1 expression on the prognosis of patients with hormone receptor-positive breast cancer.

BACKGROUND: Assessing indications for adjuvant chemotherapy (CT) in patients with hormone receptor (HR)-positive/human epidermal receptor 2 (HER2)-negative breast cancer remains a challenge for oncologists. In this study, we evaluated whether forkhead-box protein A1 (FOXA1) expression was a prognostic and predictive marker for HR-positive breast cancer. METHODS: FOXA1 expression was analyzed immunohistochemically in 239 primary breast cancers. Associations between FOXA1 expression and clinicopathological characteristics and prognosis were evaluated. RESULTS: FOXA1 expression was positively correlated with estrogen receptor (ER) (P<0.0001) and progesterone receptor (PR) expression (P=0.0011), and inversely correlated with nuclear grade (P=0.0048) and Ki67 index (P=0.0112). High FOXA1 was associated with longer recurrence-free survival (RFS) in all cases (P<0.0001) and in ER-positive cases (P<0.0001), but not in ER-negative cases. In addition, FOXA1 expression was associated with good prognosis, regardless of the Ki67 index, in HR-positive cases. FOXA1 was an independent prognostic factor on multivariate analysis in all cases and in ER-positive cases. Among HR-positive/HER2-negative cases with high FOXA1 expression, there was no difference in RFS between those given hormone therapy (HT) alone and those given CT plus HT. CONCLUSIONS: In HR-positive breast cancer, FOXA1 expression was significantly associated with good prognosis. FOXA1 expression may be a useful marker for HR-positive/HER2-negative breast cancer to identify patients with good prognosis who may not require CT.

Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions.

The use of in vitro human liver cell models is an attractive approach in toxicogenomic studies designed to analyze gene expression changes induced by a toxic chemical. However, in such studies, reliability, reproducibility and interlaboratory concordance of microarrays, as well as the choice of the most suitable cell model, remain a matter of debate. This work was aimed at evaluating the robustness of microarray technologies and the suitability of the highly differentiated human HepaRG cell line in the investigation of gene expression changes induced by a toxic compound in human liver. The influence of various experimental conditions including cell cultures grown at different test sites, different generations of microarrays, RNA analysis platforms and softwares, was tested on gene expression profiles induced by a 20h treatment with an 8mM concentration of phenobarbital as the toxic compound. As many as 1099 genes (p-value<0.01 and 1.5-fold-change), representing 74% and 30% of the signature genes detected with Agilent 22 and 44K pangenomic microarrays, respectively, were shown to be modulated in common in six independently performed experiments. The most modulated genes included both those known to be regulated by phenobarbital, such as cytochromes P450 and membrane transporters, and those involved in oxidative stress, inflammation and apoptosis, typifying a toxic insult. These data provide strong support for the use of a toxicogenomic approach for the in vitro prediction of chemical toxicity, and for the choice of human HepaRG cells as a promising model system for human hepatotoxicity testing.

Classification of psychotropic drugs by rat EEG analysis: the anxiolytic profile in comparison to the antidepressant and neuroleptic profile.

Electroencephalograms were recorded from the parietal and frontal cortex of freely moving rats held in constant vigilance by placing them in a slowly turning drum. The effects of 5 clinically effective anxiolytics, buspirone, meprobamate, phenobarbital, chlordiazepoxide and diazepam, were studied after intraperitoneal injection of different doses. After on-line fast Fourier transformation of the EEG signal, the drug effects were quantified by an Analysis of Variance. This resulted in a t profile for each drug dosage. Averaging the t profiles of all dosages of a drug results in a 'drug profile'. Averaging the drug profiles of the 5 anxiolytic drugs tested results in an 'anxiolytic profile'. This profile is characterized by a power decrease from 8 to 11 Hz and above 70 Hz and a power increase from 20 to 60 Hz. The anxiolytic profile is compared with the formerly defined antidepressant and neuroleptic profiles and can be clearly distinguished from the latter two.