Bevacizumab treatment of patients with breast cancer is associated with differential expression and up-regulation of the thyrotroph embryonic factor, TEF.

Bevacizumab (Avastin) is an approved treatment option by the European Medicines Agency (1) for more than a quarter billion women in the European Union, and despite having its indication withdrawn by the Food and Drug Administration in 2011 is still utilized in clinical trials in the United States (2, 3). We mined published microarray data (4) from the PROMIX trial to understand in an unbiased fashion genes most transcriptionally perturbed by bevacizumab administration and how this interacted with a standard anthracycline and taxane chemotherapeutic regimen, epirubicin and docetaxel. We report here the differential and increased expression of the thyrotroph embryonic factor, HLF, in the primary tumors of women treated with bevacizumab for breast cancer. We have recently described the differential expression and up-regulation of TEF in the tumors of breast cancer patients with bevacizumab. Thus, treatment with bevacizumab results in transcriptome-level differential expression and transcriptional induction of two PAR bZIP transcription factors in the tumors of patients with breast cancer.

Thyrotroph embryonic factor (TEF) is differentially expressed in high-grade serous ovarian cancers.

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of normal ovary with that of primary tumors from women diagnosed with HGSC using published microarray data (2, 3). We previously reported differential expression of the PAR-bZIP transcription factor HLF in HGSC (4). Here, we report significant differential expression of a second PAR-bZIP transcription factor, thyrotroph embryonic factor (TEF) (5) in high-grade serous ovarian tumors.

Reduction of Cellular Lipid Content by a Knockdown ofDrosophila PDP1γand Mammalian Hepatic Leukemia Factor

In exploring the utility of double-stranded RNA (dsRNA) injections for silencing thePAR-domain protein 1 (Pdp1)gene in adultDrosophila, we noticed a dramatic loss of fat tissue lipids. To verify that our RNAi approach produced the expectedPdp1knockdown, the abdominal fat tissues sections were stained with PDP1 antibodies. PDP1 protein immunostaining was absent in flies injected with dsRNA targeting a sequence common to all knownPdp1isoforms. Subsequent experiments revealed that lipid staining is reduced in flies injected with dsRNA against Pdp1γ(fat body specific) and not againstPdp1ε(predominantly involved in circadian mechanisms).DrosophilaPDP1γprotein shows a high homology to mammalian thyrotroph embryonic factor (TEF), albumin D site-binding protein (DBP), and hepatic leukemia factor (HLF) transcription factors. In an in vitro model of drug- (olanzapine-) induced adiposity in mouse 3T3-L1 cells, the mRNA content of HLF but not TEF and DBP was increased by the drug treatment. A knockdown of the HLF mRNA by transfecting the cultures with HLF dsRNA significantly reduced their lipid content. Furthermore, the HLF RNAi prevented olanzapine from increasing the cell lipid content. These results suggest that the PDP1/HLF system may play a role in physiological and drug-influenced lipid regulation.