Compelling evidence now exists for estrogen's involvement in the regulation of mood and cognitive functions. Serum estrogen levels have been shown to play an important role in the expression of psychiatric disorders such as depression and schizophrenia. We have characterized the distribution of the estrogen receptors, ERalpha and ERbeta, in the human brain and showed a preferential limbic-related expression pattern for these transcripts. The ERalpha mRNA dominates in the amygdala and hypothalamus, suggesting estrogen modulation of autonomic and neuroendocrine as well as emotional functions. In contrast, the hippocampal formation, entorhinal cortex, and thalamus appear to be ERbeta-dominant areas, suggesting a role for ERbeta in cognition, non-emotional memory, and motor functions. The role of estradiol can also be examined in regard to its relationship to other neurotransmitter systems known to be linked to specific psychiatric disorders. Estradiol has been shown to regulate the serotonin (5-HT) system, which has been strongly implicated in affective disorders. We have studied a genetic animal model of depression, and found altered 5-HT receptor mRNA levels in discrete brain regions; many of the abnormalities are reversed by estradiol treatment, especially for the 5-HT(2A) receptor subtype. The norepinephrine (NE) system is, similar to serotonin, a target for antidepressant drugs, and projects to mesocorticolimbic structures implicated in mood disorders. We have recently observed that NE neurons in the human locus coeruleus (LC) express moderate levels of both ER transcripts. The possibility of estrogen's regulating LC function has been documented in animal studies. Results from our preliminary experiments have revealed that the ERbeta mRNA is decreased in persons committing suicide, a cause of death that is highly linked to affective disorder. Follow-up studies are currently under way with a much larger population to validate these results. Overall, the discrete anatomical organization of the ER mRNAs in the human brain provide evidence as to the specific neuronal populations in which the actions of ERs could modulate mood and thus underlie the neuropathology of psychiatric disorders such as depression.
In an attempt to identify subtypes of breast cancer and pinpoint patterns of cell cycle regulatory defects associated with clinical behaviour, proliferation and other transformation associated events, a multitude of cell cycle regulatory proteins were analysed in a material of 113 primary breast cancers. Increased proliferation was observed in two different scenarios; (1) with high cyclin D1 and elevated retinoblastoma protein (pRb) phosphorylation, (cyclin D1 high tumours) or (2) with high cyclin E protein but low cyclin D1 and lack of corresponding pRb phosphorylation (cyclin E high tumours) indicative of an interrupted pRb pathway. Characteristic for cyclin E high tumours were further defects in p53, p27 and bcl-2, while c-erbB2 overexpression and c-myc amplification was found in both cyclin D1high and E high tumours. Using transfected cell lines overexpressing cyclin E, cyclin E high and D1 high tumours were mimicked and the cyclin D1 high cell line normalized the cyclin E kinase activity by an induction and redirection of p21 and p27 to the cyclin E complex whereas cyclin E high cell lines obtained increased kinase activity without redirection of inhibitors. Based on differences in genetic aberrations as well as function of the pRb node we therefore propose a model in which cyclin D1 high and cyclin E high tumours represent two alternative mechanisms to inactivate the pRb pathway and thereby achieve unrestrained growth in the tumorogenesis of breast cancer. Oncogene (2002Oncogene ( ) 21, 4680 -4690. doi:10.1038 Keywords: breast cancer; cell cycle; cyclins; cdkinhibitors; pRb pathway; proliferation IntroductionThe G1/S transition in normal cells is a thoroughly controlled checkpoint where the important decision to initiate DNA-replication or not is taken (Draetta, 1994;Weinberg, 1995). As has been obvious the last couple of years, aberrations in G1/S regulatory proteins are common in various tumours and aberrant expression of cyclin E and D1, downregulation of p16 and p27 as well as mutation of the retinoblastoma gene (Rb) has frequently been observed in several cancers and it can be hypothesized that G1/S defects might be obligatory in tumour development (Landberg and Roos, 1997;Sandhu and Slingerland, 2000).Cyclin D1 links mitogenic signals to cell cycle progression through increased phosphorylation of pRb (Lukas et al., 1996). Amplification of the encoding cyclin D1 gene, CCND1, resulting in high cyclin D1 protein content, has been observed in a significant numbers of breast cancers and together with impaired cyclin D1 protein degradation potentially cause unbalanced phosphorylation of pRb (Sherr, 1996;Russell et al., 1999). The relation between cyclin D1 and in vivo pRb phosphorylation in primary breast cancer has nevertheless not been investigated. Overexpression of cyclin D1 has been associated with ERpositivity (Michalides et al., 1996;van Diest et al., 1997), while the relation to proliferation and survival has been without consensus (Jares et al., 1997;Barnes and Gillett, 1998). Nevertheless, simila...
The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer. In addition to defects in proteins controling cell cycle checkpoints, this type of aberrations could a ect tumor growth and survival thereby in¯uencing both tumor aggressiveness and potential response to treatments. We have previously identi®ed the T1A12/mac25 protein, which is identical to the IGFBP-rP1, as a di erentially expressed gene product in breast cancer cells compared with normal cells. Here we compare the expression of IGFBP-rP1 in 106 tumor samples with known status of cell cycle aberrations and other clinicopathological data. This was done using a tumor tissue section array system that allows for simultaneous immunohistochemical staining of all samples in parallel. Cytoplasmic staining of variable intensity was observed in most tumors, 15% lacked IGFBP-rP1 staining completely, 20% had weak staining, 32% intermediate and 33% showed strong staining. Low IGFBP-rP1 was associated with high cyclin E protein content, retinoblastoma protein (pRb) inactivation, low bcl-2 protein, poorly di erentiated tumors and higher stage. There was a signi®cantly impaired prognosis for patients with low IGFBP-rP1 protein tumors. Interestingly, IGFBP-rP1 showed an inverse association with proliferation (Ki-67%) in estrogen receptor negative tumors as well as in cyclin E high tumors suggesting a separate cell cycle regulatory function for IGFBP-rP1 independent of interaction with the estrogen receptor or the pRb pathway. Oncogene (2001) 20, 3497 ± 3505.
Cerebrospinal fluid (CSF) samples obtained by consecutive lumbar puncture of 26 patients with presumed pale cerebral infarction, 66 with presumed hemorrhagic infarction, 16 with lobar hematoma, and 18 with cerebral infarction verified at autopsy, were examined with a cytological method permitting a total and differential cell count. A transitory outflow of polymorphonuclear neutrophilic leukocytes (PNL) was found in 70% of the patients with hemorrhagic infarction and lobar hematoma, with a peak three to four days after onset. The strongest PNL reaction was recorded in CSF from patients with lobar hematoma. In 75% of patients with pale infarction, no PNL or only a few PNL were found. In the autopsy group the PNL reaction in the brain as well as in the CSF was stronger in patients with hemorrhagic infarcts than in those with pale infarcts. (26:489-501, 1972) Key Words.\p=m-\Cerebrospinalfluid cytology; differential diagnosis of stroke; brain infarction; lobar hematoma; cerebrospinal fluid in cerebro-$ vascular disease.
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