Biomedical subjects

J Kononen

Publications and source records attributed to J Kononen.

48 records · Page 3Linked to original sources

PubMed1996

Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy.

PURPOSE: Up to 30% to 40% of metastases from hormone receptor-positive primary breast cancer do not respond to endocrine therapy. We studied how often hormone receptor status changes between primary and recurrent tumors and whether such a change might explain unresponsiveness to endocrine therapy. PATIENTS AND METHODS: Primary breast cancer samples and matched asynchronous recurrences were studied from 50 patients who had not received any adjuvant therapy. Estrogen receptor (ER) and progesterone receptor (PR) status was determined immunohistochemically from histologically representative formalin-fixed paraffin-embedded tumor samples. ER status was ascertained by mRNA in situ hybridization. RESULTS: Thirty-five (70%) of 50 primary tumors were positive for ER and 30 (60%) for PR. Hormone receptor status of the recurrent tumor differed from that of the primary tumor in 18 cases (36%). Discordant cases were due to the loss of ER (n = 6), loss of PR (n = 6), or loss of both receptors (n = 6). Receptor-negative primary tumors were always accompanied by receptor-negative recurrences. Among 27 patients with ER-positive primary tumors, loss of ER was a significant predictor (P = .0085) of poor response to subsequent endocrine therapy. Only one of eight patients (12.5%) with lost ER expression responded to tamoxifen therapy, whereas the response rate was 74% (14 of 19) for patients whose recurrent tumors retained ER expression. CONCLUSION: Loss of ER expression in recurrent breast cancer should be considered as a cause for poor response to endocrine therapy in primarily ER-positive patients. We conclude that analysis of recurrent tumor samples may improve the predictive value of ER and PR assays.

Adult↗

PubMed1996

Expression of topoisomerase IIalpha is associated with rapid cell proliferation, aneuploidy, and c-erbB2 overexpression in breast cancer.

The role of molecular markers predicting the response to cytotoxic chemotherapy is not established. A potential predictive factor, topoisomerase IIalpha, is a target for certain cytotoxic drugs, and its concentration has been shown to correlate with chemosensitivity in vitro. We evaluated expression of topo IIalpha immunohistochemically in 230 breast cancer samples and studied its association with known clinicopathological factors and factors previously shown to predict response to cytotoxic drugs. Topo IIalpha protein expression was found in 0.6 to 39.4% (10.6 +/- 7.9%, mean +/- SD) of breast carcinoma cells, whereas expression was undetectable in nonmalignant breast epithelium. Topo IIalpha protein expression correlated well with semi-quantitative mRNA in situ hybridization (P = 0.007). A significant association was found between the proportion of topo-IIalpha-positive cells and low estrogen and progesterone receptor content (P<0.0001), high grade (P<0.0001), DNA aneuploidy (P=0.003), and c-erbB-2 oncoprotein overexpression (P<0.0001). Topo IIalpha expression was not associated with clinical variables, such as age of the patient, primary tumor size, or axillary nodal status. A highly significant linear correlation was found between topo IIalpha and tumor proliferation rate (S-phase fraction, r=0.46; P<0.0001). Because hormone receptors, grade, and ploidy are associated with tumor proliferation rate, topo IIalpha expression was adjusted for S-phase fraction to reveal the proliferation-independent clinopathological associations. According to the analysis of co-variance, only aneuploidy (P=0.0003) and c-erb-2 overexpression (P=0.01) were associated with proliferation-adjusted expression of topo IIalpha. In conclusion, the close association of Topo IIalpha with other potential predictive factors (tumor proliferation rate, c-erbB-2 oncoprotein) suggests that topo IIalpha, having a defined role as a target for cytotoxic drugs, may be a valuable predictor of response to chemotherapy.

Adult↗

PubMed1995

Effects of aging on the expression of neurotrophins and their receptors in the rat pituitary gland.

We studied the effect of aging on the mRNA levels of neurotrophins and their receptors in the rat pituitary gland using in situ hybridization. In 2-month-old rats, mRNA for brain derived neurotrophic factor (BDNF) was observed in the anterior and intermediate lobes of the pituitary. TrkB and trkC, the putative receptors for BDNF and neurotrophin-3, were also expressed in the pituitary. In contrast, trk mRNA could not be detected in any of the pituitaries studied. Aging did not affect BDNF mRNA levels. In 2-year-old rats, trkB and trkC mRNA levels were decreased in the anterior lobe. TrkB mRNA levels decreased also in the neural lobe. These results show that although the expression of BDNF does not change during aging in the pituitary, expression of trkB and trkC mRNAs are altered in senescence. These changes may reflect overall impairments in pituitary endocrine functions in old age or they may be associated with morphological alterations in pituitary innervation.

Aging↗

PubMed1995

Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferation.

The expression of peripheral-type benzodiazepine receptor (PBR) and diazepam binding inhibitor (DBI) were studied in human astrocytic tumors using immunocytochemistry and in situ hybridization. Both PBR and DBI were prominently expressed in neoplastic cells, whereas in normal brain their amount was low or undetectable. Immunocytochemical double staining demonstrated that PBR and DBI were present in the same cells, suggesting that DBI may act in an autocrine manner in these cells. Analysis of 86 cases showed that PBR expression was statistically significantly associated with tumor malignancy grade (P = 0.004) and the proliferative index as determined by immunocytochemistry with the MIB-1 antibody (P = 0.004). Patients having tumors with high levels of PBR-immunoreactive cells had a shorter life expectancy than patients whose tumors showed lower PBR contents (P = 0.024). In conclusion, these results show that PBR expression is higher in neoplastic cells than in normal brain tissue. They also suggest that PBR immunocytochemistry might be useful in evaluating malignancy in brain tumors.

Adolescent↗

PubMed1995

Induction of immediate early gene mRNAs and proteins by hCG in interstitial cells of rat testis.

In the present study we have investigated the induction of immediate early gene (IEG) c-fos, c-jun, junB and junD mRNAs and proteins in interstitial cells of rat testis after hCG treatment in vivo using in situ hybridization and immunocytochemistry. The basal levels of all IEGs were barely detectable with our methods. A prominent induction of c-fos, c-jun and junB mRNAs and proteins in Leydig cells was seen after hCG treatment. The induction of these IEG mRNAs and proteins demonstrates that their expression is an early transcriptional response to the extracellular stimulus of hCG and that they are involved in transcriptional processes which may mediate the effects of LH on cellular adaptive responses or steroid biosynthesis.

Animals↗

PubMed1995

Neuronal regulation of c-fos, c-jun, and junB immediate-early genes in rat adrenal medulla.

We have applied in situ hybridization histochemistry, Northern analysis, and immunocytochemistry to study the regulation of the immediate-early gene (IEG) c-fos, c-jun, and junB mRNAs and the respective proteins in the rat adrenal medulla. Electrophoresis mobility shift assay was used to examine changes in AP-1 DNA binding activity. In nontreated rats the mRNA and protein levels for these three IEGs were low. Reflex stimulation of adrenal medulla elicited by a single capsaicin injection induced a rapid and marked elevation in the mRNA levels for these IEGs. Stimulation with nicotine also caused a drastic increase in the mRNA levels, whereas muscarine only induced moderate elevations. c-fos and c-jun were induced strongly in adrenaline cells and only weakly in noradrenaline cells. junB was upregulated mainly in adrenaline cells. The AP-1 DNA binding activity was low in control adrenals, whereas a marked increase was observed after nicotine treatment. Treatment of the animals with a nicotinic (chlorisondamine) or a muscarinic (atropine) receptor antagonist did not change the expression of IEGs studied. The combination of the two drugs, however elevated the mRNA levels for all three IEGs, especially for junB. Pretreatment of the rats with chlorisondamine alone or in combination with atropine diminished the capsaicin-induced increase in c-fos, whereas atropine alone was less efficient. Increase in c-jun mRNA was not affected by these drugs. The capsaicin-induced elevation of junB mRNA levels was not influenced by chlorisondamine or atropine alone, whereas both combined potentiated the effect of capsaicin. The present results demonstrate that neurotransmitters released from splanchnic nerve terminals induce expression of c-fos, c-jun, and junB in adrenal chromaffin cells which results in increased AP-1 DNA binding activity. Although stimulation of both nicotinic and muscarinic cholinergic receptors may mediate the induction of these IEGs, it is possible that also another neurotransmitter(s), in addition to ACh, released from splanchnic nerve terminals is involved in the regulation of their expression, especially of c-jun and junB.

Adrenal Medulla↗

PubMed1994

Neurotrophins and their receptors in the rat pituitary gland: regulation of BDNF and trkB mRNA levels by adrenal hormones.

We studied the expression of messenger ribonucleic acids (mRNAs) for neurotrophins and neurotrophin receptors in the rat pituitary gland and examined the influence of adrenal hormones on their mRNA levels, using in situ hybridization and Northern blot analysis. The only neurotrophin present at detectable levels in the pituitary was brain-derived neurotrophic factor (BDNF), which was observed in the anterior and intermediate lobes. Several transcripts of the putative receptor for BDNF, trkB, were present in the anterior and posterior lobes of the pituitary. A low amount of trkC mRNA was found in both the anterior and the intermediate lobe. Dexamethasone treatment decreased both BDNF and trkB mRNA levels in the anterior lobe of the pituitary. Adrenalectomy had no effect on trkB expression, but it decreased BDNF mRNA levels in comparison to the control animals. This effect could not be reversed by dexamethasone substitution, suggesting that BDNF, mRNA levels may be regulated not only by glucocorticoids but also by other adrenal hormones. These results demonstrate that BDNF, trkB and trkC are expressed in the pituitary gland and that glucocorticoids and possibly other adrenal hormones may modulate pituitary functions by regulating the expression of neurotrophic factors and their receptors. Whether BDNF acts as a secreted hormone, a trophic factor, or has autocrine/paracrine functions within the pituitary through its receptor, trkB, remains to be studied.

Animals↗

PubMed1994

Induction of multiple immediate early genes in rat hypothalamic paraventricular nucleus after stress.

We have previously demonstrated that stress causes a rapid and transient elevation in the expression of the immediate early genes (IEGs) c-fos and the members of the jun gene family in the brain. Here we demonstrate the effect of stress on the expression of fra-1, fra-2 and recently characterized IEGs encoding zinc finger containing proteins. Capsaicin-induced stress caused a rapid and transient induction of NGFI-A, NGFI-B, fra-2 and TIS11 in the hypothalamic paraventricular nucleus. The NGFI-A mRNA levels were also slightly increased in the cerebral cortex and striatum. The expression of fra-1, NGFI-C, egr-3 and Nurr1 did not show any change. The time course of the induction of NGFI-A, NGFI-B, fra-2 and TIS11 was similar to that previously observed with c-fos and the members of the jun family. The present results suggest that NGFI-A, NGFI-B, fra-2 and TIS11 mediate some of the stress-induced changes of the PVN at the level of gene expression. Although the genes of the NGFI/egr family encode structurally similar proteins, they seem to be regulated differentially and thus have diverse roles in regulating gene expression in the brain.

Animals↗

PubMed1994

Stage-specific expression of pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA in the rat seminiferous tubules.

We have used in situ hybridization and Northern blot analysis with oligonucleotide probe to characterize the site of pituitary adenylate cyclase-activating polypeptide (PACAP) synthesis in the rat testis. We observed strong hybridization signal in one third of the cross-sections of the seminiferous tubules, whereas some tubules were devoid of hybridization signal, thus suggesting that PACAP mRNA is expressed in a stage-specific manner. More detailed analysis showed that PACAP mRNA was present in round spermatids at stages III-VII of the cycle. Northern blot hybridization to RNAs extracted from samples of seminiferous tubules at different stages of the epithelial cycle confirmed that expression of PACAP mRNA is restricted to specific stages of the cycle. The highest amount of PACAP mRNA was detected at stages V to early -VII of the cycle, whereas very low levels of mRNA were present at stages I-II and IX-XIV. The present results demonstrate that PACAP mRNA is expressed in the developing germ cells. This suggests that PACAP may function as a paracrine or autocrine regulatory factor for the Sertoli and germ cells, with a specific function during early spermiogenesis, shortly before the onset of nuclear elongation, at the last period of haploid gene activity.

Animals↗

PubMed1993

Glucocorticoid receptor colocalization with pituitary hormones in the rat pituitary gland.

The presence of glucocorticoid receptor (GR) in the anterior lobe of the pituitary gland has previously been demonstrated, but the exact cell types expressing GR have not yet been characterized. In this study, we demonstrate the colocalization of GR and pituitary hormones in the rat pituitary gland by using an immunocytochemical double-labelling method. The majority of anterior lobe corticotropin-immunoreactive and growth hormone-immunoreactive cells contained GR-like immunoreactivity. Cells of the intermediate lobe showed intensive ACTH-like immunoreactivity but did not express GR. The glycoprotein hormones thyroid-stimulating hormone, follicle-stimulating hormone and luteinizing hormone were colocalized with GR to a lesser degree; approximately one-half of the cells exhibited immunoreactivity to these hormones contained GR. By contrast, only a minority of the prolactin-immunoreactive cells expressed GR. Our results suggest that glucocorticoids may differentially regulate the secretion and/or synthesis of these pituitary hormones by directly affecting the hormone-producing cells of the anterior pituitary.

Animals↗

PubMed1992

Fos-like immunoreactivity in the rat hypothalamic-pituitary axis after immobilization stress.

The effect of immobilization stress on the expression of the protooncogene c-fos in the rat pituitary and hypothalamus was investigated immunohistochemically using different polyclonal antibodies raised against the c-fos protein (Fos). After a 4 h immobilization, Fos-like immunoreactivity (Fos-LI) increased substantially in the parvocellular part of the paraventricular nucleus and in the intermediate and anterior lobe of the pituitary. The majority of the Fos-immunoreactive cells in the pituitary contained corticotropin, which was demonstrated by immunohistochemical double-staining. Since the paraventricular nucleus contains a large number of glucocorticoid receptor immunoreactive cells, the effect of a synthetic glucocorticoid, dexamethasone, on the induction of Fos-LI was studied. Dexamethasone treatment before immobilization considerably reduced the stress-induced expression of Fos-LI in the anterior and intermediate lobe of the pituitary but did not alter the induction of Fos-LI in the paraventricular nucleus. The present results demonstrate that immobilization stress induces Fos-LI both in the hypothalamus and in the pituitary, suggesting that Fos may be involved in regulating the synthesis of different mediators of stress response, such as CRF- and POMC-derived peptides. Apparently glucocorticoids do not directly repress c-fos expression, since dexamethasone did not affect the induction of Fos-LI in the paraventricular nucleus. The reduction of stress-induced Fos-LI in the pituitary by dexamethasone is possibly due to the diminished release of CRF factor from the paraventricular neurons.

Adrenocorticotropic Hormone↗

PubMed1990

Circadian rhythm in c-fos-like immunoreactivity in the rat brain.

The circadian variation in the expression of Fos protein(s) in the rat brain was studied immunohistochemically. The number of Fos-immunoreactive nuclei was statistically increased in the hippocampus and caudate putamen after the onset of darkness. Unlike the cells of the hippocampus and putamen the cells in the suprachiasmatic nucleus displayed a circadian variation with the lowest values during the nighttime and the highest in the morning. As the circadian rhythm of Fos expression in the normal rat brain may correlate with that reported for ACTH and corticosteroids, the results suggest that the fos gene is involved in mediating physiological activation of specific neuron populations of intact rats.

Amino Acid Sequence↗