Identification of estrogen target genes in human neural cells

In mammals, estrogens have a multiplicity of effects ranging from control of differentiation of selected brain nuclei, reproductive functions, sexual behavior. In addition, these hormones influence the manifestation of disorders like depression and Alzheimer's. Study of the cells target for the hormone has shown that estrogen receptors (ERs) are expressed in all known neural cells, including microglia. In view of the potential interest in the use of estrogens in the therapy of several pathologies of the nervous system, it would be of interest to fully understand the mechanism of estrogen activity in the various neural target cells and get an insight on the molecular means allowing the hormone to display such a variety of effects. We have proposed the use of a reductionist approach for the systematic understanding of the estrogen activities in each specific type of target cell. Thus, we have generated a model system in which to study the activation of one of the known (ERs), estrogen receptor alpha. This system allowed us to identify a number of novel genes which expression may be influenced following the activation of this receptor subtype by estradiol (E-2). We here report on data recently obtained by the study of one of these target genes, nip2, which encodes a proapoptotic protein product. We hypothesize that nip2 might be an important molecular determinant for estrogen anti-apoptotic activity in cells of neural origin and represents a potential target for drugs aimed at mimicking the E-2 beneficial effects in neural cells. (C) 2000 Elsevier Science Ltd. All rights reserved

Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease, and Fanconi anemia (FA) gene mutations and transcriptional repression are common. Invasive tumor behavior is associated with poor outcome, but relevant pathways triggering invasion are poorly understood. There is a significant need to improve our understanding of genetic pathways and molecular mechanisms driving advanced tumor phenotypes, to develop tailored therapies. Here we sought to investigate the phenotypic and molecular consequences of FA pathway loss in HNSCC cells. EXPERIMENTAL DESIGN: Using sporadic HNSCC cell lines with and without FA gene knockdown, we sought to characterize the phenotypic and molecular consequences of FA deficiency. FA pathway inactivation was confirmed by the detection of classic hallmarks of FA following exposure to DNA cross-linkers. Cells were subjected to RNA sequencing with qRT-PCR validation, followed by cellular adhesion and invasion assays in the presence and absence of DNA-dependent protein kinase (DNA-PK) and Rac1 inhibitors. RESULTS: We demonstrate that FA loss in HNSCC cells leads to cytoskeletal reorganization and invasive tumor cell behavior in the absence of proliferative gains. We further demonstrate that cellular invasion following FA loss is mediated, at least in part, through NHEJ-associated DNA-PK and downstream Rac1 GTPase activity. CONCLUSIONS: These findings demonstrate that FA loss stimulates HNSCC cell motility and invasion, and implicate a targetable DNA-PK/Rac1 signaling axis in advanced tumor phenotypes

Human Papillomavirus Oral- and Sero- Positivity in Fanconi Anemia

High-risk human papillomavirus (HPV) is prevalent and known to cause 5% of all cancers worldwide. The rare, cancer prone Fanconi anemia (FA) population is characterized by a predisposition to both head and neck squamous cell carcinomas and gynecological cancers, but the role of HPV in these cancers remains unclear. Prompted by a patient-family advocacy organization, oral HPV and HPV serological studies were simultaneously undertaken. Oral DNA samples from 201 individuals with FA, 303 unaffected family members, and 107 unrelated controls were tested for 37 HPV types. Serum samples from 115 individuals with FA and 55 unrelated controls were tested for antibodies against 9 HPV types. Oral HPV prevalence was higher for individuals with FA (20%) versus their parents (13%; p = 0.07), siblings (8%, p = 0.01), and unrelated controls (6%, p ≤ 0.001). A FA diagnosis increased HPV positivity 4.84-fold (95% CI: 1.96-11.93) in adjusted models compared to unrelated controls. Common risk factors associated with HPV in the general population did not predict oral positivity in FA, unlike unrelated controls. Seropositivity and anti-HPV titers did not significantly differ in FA versus unrelated controls regardless of HPV vaccination status. We conclude that individuals with FA are uniquely susceptible to oral HPV independent of conventional risk factors

Estrogens, apoptosis and cells of neural origin

In mammals, estrogens have a multiplicity of effects in all known neural cells. We review here some of the mechanisms enabling estrogens to differentiate their influence on neural targets. In view of the potential interest in the use of estrogens in the therapy of several pathologies of the nervous system, we have proposed the use of a reductionist approach for the systematic understanding of estrogen activities in each specific type of target cell. We have therefore generated a model system in which to study the activation of one of the known estrogen receptors: estrogen receptor alpha. This system allowed us to identify a number of novel genes, the expression of which may be influenced following the activation of this receptor subtype by estradiol. We here report on preliminary data obtained by the study of one of these target genes, nip2, which encodes a proapoptotic protein product. We hypothesize that Nip2 might be an important molecular determinant for estrogen anti-apoptotic activity in cells of neural origin

Expression of the estrogen-regulated gene Nip2 during rat brain maturation

The present study stems from previous observations demonstrating that in the neuroblastoma cell line SK-ER3 the mRNA content of the pro-apoptotic gene Nip2 is decreased following treatment with estradiol. We investigate the content of Nip2 mRNA during the maturation of rat embryo brain and we show that Nip2 mRNA is very low at embryo day 15 and steadily increases up to day 20. At day 21 Nip2 mRNA is decreased almost to the low levels observed in the mature brain. Studies in neurons from rat embryo at day 18 show that Nip2 mRNA content is significantly decreased by exposure to estradiol at 1 nM concentration demonstrating that the observations previously done in the SK-ER3 neuroblastoma cell line can be reproduced in neurons in culture. The finding that estrogens may modulate the activity of Nip2 gene activity may be of relevance not only with regard to the effects of estradiol on brain maturation, but also for the understanding of the neuroprotective effects recently described for this hormone