Genomics of Signaling Crosstalk of Estrogen Receptor α in Breast Cancer Cells

BACKGROUND: The estrogen receptor alpha (ERalpha) is a ligand-regulated transcription factor. However, a wide variety of other extracellular signals can activate ERalpha in the absence of estrogen. The impact of these alternate modes of activation on gene expression profiles has not been characterized. METHODOLOGY/PRINCIPAL FINDINGS: We show that estrogen, growth factors and cAMP elicit surprisingly distinct ERalpha-dependent transcriptional responses in human MCF7 breast cancer cells. In response to growth factors and cAMP, ERalpha primarily activates and represses genes, respectively. The combined treatments with the anti-estrogen tamoxifen and cAMP or growth factors regulate yet other sets of genes. In many cases, tamoxifen is perverted to an agonist, potentially mimicking what is happening in certain tamoxifen-resistant breast tumors and emphasizing the importance of the cellular signaling environment. Using a computational analysis, we predicted that a Hox protein might be involved in mediating such combinatorial effects, and then confirmed it experimentally. Although both tamoxifen and cAMP block the proliferation of MCF7 cells, their combined application stimulates it, and this can be blocked with a dominant-negative Hox mutant. CONCLUSIONS/SIGNIFICANCE: The activating signal dictates both target gene selection and regulation by ERalpha, and this has consequences on global gene expression patterns that may be relevant to understanding the progression of ERalpha-dependent carcinomas

Measurement of the hypotenuse of the vertical optic nerve head cup with spectral-domain optical coherence tomography for the structural diagnosis of glaucoma

Fabio Lavinsky,1,2 Camila Zanella Benfica,2 Nédio Castoldi,2 Anne Elise Cruz do Carmo Chaves,2 Paulo Augusto de Arruda Mello1 1Department of Ophthalmology, Paulista School of Medicine, São Paulo Hospital, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil; 2Department of Ophthalmology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil Purpose: To evaluate the hypotenuse of the vertical optic nerve head cup (HVOC), measured using the length and depth of the cup obtained with enhanced depth imaging spectral-domain optic coherence tomography (SD-OCT), as a biomarker for glaucoma diagnosis. Methods: This was a prospective cross-sectional study of patients with glaucoma and controls. SD-OCT was performed in all participants to assess average circumpapillary retinal nerve fiber layer (RNFL) thickness. A vertical B-scan of the optic nerve head (ONH) was obtained for HVOC measurement. The length and depth of the optic nerve cup formed the sides of a right triangle that were used to calculate the HVOC. Participants also underwent standard automated perimetry. Results: One hundred and fifty-six eyes were divided into three groups: mean deviation (MD) <-7 dB (60 eyes); MD ≥-7 dB (74 eyes); and healthy subjects (22 eyes). The mean (SD) HVOC in these groups was 1,419.8 (347.2) µm, 1,234.6 (258.8) µm, and 685.79 (315.4) µm (P<0.01), respectively. In the secondary structure–function analysis, only discs with a vertical diameter of 1.51–2.00 mm were included (120 eyes). The HVOCs were divided into four percentile groups, with the following means: 940, 1,128, 1,390, and 1,662 µm. There was a significant difference in MD between percentile groups 1 and 3 (P<0.03), 1 and 4 (P<0.001), 2 and 3 (P<0.02), and 2 and 4 (P<0.001). RNFL thickness differed among all percentile groups (P<0.001). Conclusion: HVOC may provide an additional morphometric biomarker for the structural evaluation of ONH remodeling in glaucoma. Keywords: glaucoma diagnosis, optic nerve head, visual fields, ocular imagin