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PubMed1997

Inverse correlation of cell proliferation and expression of progesterone receptors in tumor spheroids and monolayer cultures of human meningiomas.

OBJECTIVE: The progesterone receptor (PgR) can be detected in 60 to 70% of meningiomas using immunohistochemistry] in situ. Whereas in monolayer tissue cultures the PgR is only rarely expressed, we were able recently to demonstrate the preservation of the PgR in fragment spheroid cultures of meningiomas. The aim of the present study was to evaluate the stability of PgR expression in meningioma spheroids in vitro and the correlation of PgR expression and cell proliferation in spheroids and whether meningioma cells reaggregated to spheroids from monolayer cultures to reexpress the PgR again. METHODS: Tumor fragment spheroids (Weeks 1-6) and cell monolayers (Passages 1 and 3) of 15 PgR-positive meningiomas were investigated by immunohistochemistry for the expression of PgRs and their proliferative activity, as demonstrated by positivity for the proliferation-related antigen Ki-67. To study PgR reexpression in reaggregated spheroids, Northern blots were performed. In addition, a reverse transcriptase-polymerase chain reaction technique was established and evaluated in combination with immunohistochemistry. Growth of meningioma spheroids was quantified in the presence of progesterone and the specific antagonist onapristone. RESULTS: The PgR remained stable in spheroids for 6 weeks in 9 of 13 cases that were able to be evaluated. All tumor fragment spheroids exhibited a proliferation index of 5 to 40% Ki-67-positive cells. Monolayer cell cultures, on the other hand, failed to express PgRs but revealed higher proliferation indices (40-90%) to a significant extent. The detection of PgR messenger ribonucleic acid in reaggregated spheroids by means of reverse transcriptase-polymerase chain reaction correlated to the nuclear expression of PgR in immunohistochemistry. Neither progesterone nor its antagonist onapristone altered spheroid growth in vitro. CONCLUSION: The expression of the PgR in meningiomas is preserved in spheroid cultures with low proliferation indices for at least 6 weeks, whereas monolayer cell cultures with a high proliferative activity lack PgR expression. The inverse pattern of Ki-67-positive cells in the outer regions of the spheroids and PgR-expressing tumor cells in the spheroid centers leads us to the conclusion that proliferating meningioma tumor cells do not express PgRs. This might also explain why tumor cell growth in vitro was neither affected by progesterone nor by onapristone. Monolayer cell cultures can be reaggregated to spheroids, the consequence being a reexpression of PgRs and, therefore, a down-regulation of proliferation.

Antineoplastic Agents↗
PubMed1999

The normal breast epithelium of women with breast cancer displays an aberrant response to estradiol.

Breast epithelial response to estradiol may play an important role in breast cancer etiology. We have examined the relationship between serum estradiol and progesterone levels and normal breast epithelial expression of estrogen receptor (ER) alpha, progesterone receptor (PgR), and epithelial proliferation (as reflected by the Ki-67 labeling index) in 121 women (50 newly diagnosed breast cancer cases and 71 benign breast disease controls). Simultaneous samples of grossly normal breast tissue and venous blood were obtained from women undergoing breast surgery. Serum estradiol and progesterone levels were measured by radioimmunoassay; breast epithelial ER, PgR, and Ki-67 expression was measured by immunohistochemistry. Linear regression, controlled for patient age and ductal and lobular composition of the tissue, showed that the breast epithelium of control women displayed an inverse correlation between serum estradiol and ER-alpha, which was not seen in case women (P for the difference in regression slopes = 0.001). PgR expression displayed a significant positive correlation with serum estradiol in cases, but not in controls. Epithelial proliferation had no relationship to either estradiol or progesterone in both cases and controls but showed an inverse relationship with ER in controls and a direct relationship in cases (P for the difference in regression slopes = 0.066). These results suggest a dysregulation of hormonal response in the normal breast epithelium of high-risk women, with lack of regulation of ER by estradiol, increased estrogen responsiveness as reflected by PgR expression, and a dissociation of ER expression and proliferative response.

Adult↗
PubMed1992

Estrogen dependent regulation of estrogen receptor gene expression in normal mammary gland and its relationship to estrogenic sensitivity.

In the present study, we have examined the relationship between estradiol (E2)-dependent regulation of estrogen receptor (ER) gene expression in normal mammary glands and its relationship to progesterone receptor (PgR) gene expression using tissues from E2-sensitive and -insensitive states. Estradiol caused a time-dependent decrease in ER mRNA levels in E2-sensitive mammary glands reaching a maximum at approx 6 h, at which time the levels of PgR mRNA also reached a maximum. In contrast, in E2-insensitive mammary glands, there was no E2-dependent decrease in ER mRNA at all times tested. Experiments using dissociated cells revealed that although the epithelial cells of mammary glands from both E2-sensitive and -insensitive states contained ER mRNA, in the intact E2-sensitive mammary glands, it was the nonepithelial ER that was decreasing in response to E2. Since the epithelial cells of normal mammary glands are the primary target for E2-dependent PgR synthesis, our studies suggest that a positive correlation between E2-dependent PgR gene expression and E2-dependent downregulation of ER may simply be coincidental and may not bear any true biological relationship.

Animals↗
PubMed2000

Immunohistochemical analysis of pleomorphic lobular carcinoma: higher expression of p53 and chromogranin and lower expression of ER and PgR.

AIMS: Pleomorphic lobular carcinoma of the breast is a histological variant of infiltrating lobular carcinoma with a poor prognosis. The aim of this study is to investigate the immunohistochemical profile of this distinctive breast carcinoma in comparison with the classical type. The expression of cytokeratin, epithelial membrane antigen, gross cystic disease fluid protein-15, chromogranin, oestrogen and progesterone receptors and p53 oncoprotein was investigated to examine whether the expression of these markers correlates with the aggressiveness of this variant. METHODS AND RESULTS: Sections from 10 cases of pleomorphic lobular carcinomas were reviewed and examined for the expression of cytokeratin of high and low molecular weight, epithelial membrane antigen (EMA), gross cystic disease fluid protein-15 (GCDFP-15), chromogranin, oestrogen (ER) and progesterone receptors (PgR), and p53 oncoprotein. Immunohistochemical staining was performed on paraffin wax embedded sections. Ten cases of classical lobular carcinomas were used for comparison. A semiquantitative count of the percentage of positive tumour cells was recorded. Pleomorphic lobular carcinomas have most of the characteristic histological features of the classical type but have nuclear anaplasia and abundant granular cytoplasm. Clinically they exhibited poor prognosis and a high frequency of nodal metastases. All of the pleomorphic lobular carcinomas expressed low and high molecular weight keratin, EMA, and GCDFP-15, eight cases expressed nuclear p53 at a range between 10% and 45%. All cases expressed chromogranin (3-5%). ER and PgR were weakly positive in two cases and negative in eight cases. Classical infiltrating lobular carcinomas were all positive for cytokeratin, EMA, ER and PgR and negative for GCDFP-15. Only five cases of classical lobular carcinoma expressed p53 positivity with up to 5% nuclear staining while chromogranin showed less expression (1-2%). CONCLUSION: Pleomorphic lobular carcinoma exhibits distinct cellular features with apocrine differentiation, higher expression of chromogranin and p53 protein and lower ER and PgR in comparison with classical lobular carcinomas. Determination of p53 overexpression and reduced or absent expression of ER and PgR may help predict the behaviour of this variant of lobular carcinoma.

Aged↗
PubMedDate not supplied

Does sex steroid receptor status have any prognostic or predictive significance in brain astrocytic tumors?

Formalin-fixed paraffin-embedded tumor specimens from 90 patients with supratentorial astrocytic brain tumors were immunostained following microwave pretreatment using monoclonal antibodies against estrogen receptor (ER), progesterone receptor (PgR), and PS2 protein (PS2) and the streptavidin/peroxidase method. The immunohistochemical analysis was scored in a semiquantitative fashion incorporating both the intensity and distribution of specific staining (SCORE) and the immunohistochemical results were correlated with histologic grade of tumors and patient's sex and age. Strong PgR nuclear immunopositivity was observed in 27 of 46 (59%) glioblastomas, in 9 of 20 (45%) anaplastic astrocytomas, and in 2 of 24 (8%) astrocytomas. The mean PgR score was 18.5 in glioblastomas, 11.3 in anaplastic astrocytomas, and 0.9 in astrocytomas. The expression of PgR immunoreactivity appeared to be dependent on the age and independent of the sex of patients. All tumors were negative for ER and PS2 protein. Normal astrocytes remained consistently negative for both sex steroid receptors and PS2. Our findings indicate a consistent expression of PgR in a number of poorly differentiated tumors including glioblastomas and anaplastic astrocytomas contrasting with the low PgR score values found in benign astrocytomas. The absence of ER and PS2 immunoreactivities supports the hypothesis that estrogen receptor in astrocytic tumors is probably truncated. However, regional tumor heterogeneity may be a limiting factor for the use of ER, PgR, PS2 immunohistochemistry in the evaluation of routine pathology specimens examination.

Adolescent↗
PubMed2004

Transcription factor accessibility and histone acetylation of the progesterone receptor gene differs between parental MCF-7 cells and a subline that has lost progesterone receptor expression.

The human progesterone receptor (PgR) gene has a complex promoter that produces alternate mRNAs encoding the PgRA (94 kDa) and PgRB (120 kDa) protein isoforms. Expression of PgR is induced by estradiol (E(2)) in the breast, reproductive tract and many cell lines despite the lack of a classical estrogen responsive element (ERE) in the promoter regions. We employed chromatin immunoprecipitation (ChIP) to analyze the sites of estrogen receptor alpha (ERalpha) and Sp1 occupancy of the PgR promoters in vivo. We also assessed the functional relevance of histone acetylation levels on the accessibility of transcription factors to the promoter and subsequent hormone-induced transcription. We utilized MCF-7 human breast cancer cells that express PgR in response to E(2) and the MCF-7 derived C4 cell strain that has lost PgR expression as a model system. We found that promoter-wide levels of histone acetylation were not decreased in C4 cells, but that access was partially blocked for Sp1 and completely blocked for ERalpha. The basal level of histone acetylation at six localized regions of the promoter did show some differences between cell lines, but it did not correlate with transcription factor binding. Furthermore, we found only a modest and highly localized change in histone acetylation levels in response to E(2) at only one of three sites of ERalpha binding in MCF-7 cells. This was at the B1 site at the distal 5' end of the promoter. This site also showed a significant decrease in basal histone acetylation in C4 compared to MCF-7 cells. We speculate that the histone acetylation level at this site may be a marker for chromatin structure that affects the access of transcription factors to the whole promoter.

Acetylation↗
PubMed2025

Progesterone receptor isoform modulation via enhancer activation regulates progesterone signaling in endometrial stromal cells.

OBJECTIVE: To investigate enhancer-mediated regulation of progesterone receptor (PGR) isoforms, PGR-A and PGR-B, in human endometrial stromal cells, and to determine how isoform modulation shapes the progesterone-responsive transcriptome and cistrome relevant to endometrial function. DESIGN: A clustered regularly interspaced short palindromic repeats-based functional genomic screen was used to identify distal enhancers in telomerase-immortalized human endometrial stromal cells. Subsequent clustered regularly interspaced short palindromic repeats targeting of identified enhancers and the PGR promoter was used to modulate PGR isoform balance and assess functional consequences. SUBJECTS: None. EXPOSURE: Engineered endometrial stromal cells were treated with medroxyprogesterone acetate or vehicle. MAIN OUTCOME MEASURES: PGR isoform expression was assessed by western blot, the progesterone-responsive transcriptome was characterized by bulk ribonucleic acid sequencing, and the PGR cistrome was characterized by Cut&Run. RESULTS: Two distal PGR enhancers were identified in endometrial stromal cells located approximately 60 and 220 kb upstream of the PGR transcription start site. Clustered regularly interspaced short palindromic repeats-based activation of these enhancers upregulated both PGR-A and PGR-B, whereas promoter activation primarily upregulated PGR-B. Bulk ribonucleic acid sequencing revealed that shifting the PGR isoform balance altered the progesterone-regulated transcriptome: PGR-A/B-equivalent cells exhibited proinflammatory gene signatures, whereas PGR-B-dominant cells demonstrated suppression of inflammatory signaling and altered cell cycle programs. The PGR Cut&Run profiling revealed distinct genomic binding patterns associated with each isoform profile. Integration of the PGR cistrome with chromatin interaction maps suggested that these isoforms directly regulate distinct gene subsets involved in inflammation and fibrosis. Mechanistically, estrogen receptor alpha (ESR1) indirectly activated PGR-A expression, potentially through recruitment of Forkhead box protein O1 (FOXO1) at the distal enhancer, suggesting a noncanonical, enhancer-mediated mechanism of PGR regulation. CONCLUSIONS: Distal enhancers regulate the PGR isoform balance and shape the progesterone-responsive transcriptome in human endometrial stromal cells. This enhancer-mediated mechanism expands current models of PGR regulation beyond promoter-level control and may offer potential therapeutic targets to restore normal progesterone responsiveness in conditions marked by PGR isoform imbalance.

Humans↗
PubMed1998

Establishment and characterization of three new breast-cancer cell lines.

We have established and characterized 3 new breast-cancer cell lines from pleural effusions of patients with advanced breast cancer. All 3 cell lines, designated IBEP-1, IBEP-2 and IBEP-3, showed typical ultrastructural characteristics of epithelial mammary tumor cells. Electron microscopy showed, among other characteristics, the presence of numerous microvilli, desmosomal junctions, intracytoplasmic duct-like vacuoles, well-developed endoplasmic reticulum and large nuclei. Immunohistochemical and biochemical studies revealed that the 3 cell lines expressed cytokeratin, epithelial membrane antigen, CEA and CA 15-3, but all showed negative immunoreaction for vimentin. On the other hand, other antigens (LEU-M1, GCDFP 15, c-erbB-2) were expressed by some of the cell lines, but in a variable manner. Ploidy studies confirmed the neoplastic origin of the cell lines. The doubling times were 68 hr for IBEP-1, 29 hr for IBEP-2 and 39 hr for IBEP-3. Only IBEP-2 cells expressed estrogen receptors (ER+), which were down-regulated after preincubation with E2, but they did not express progesterone receptors (PgR-). IBEP-1 and IBEP-3 cells were ER- but expressed PgR (PgR+). In these 2 cell lines, PgR were down-regulated after pre-incubation of the cells with progesterone (10(-8) M) for 24 hr. Estradiol (E2) increased the proliferation rate of IBEP-2 cells and progesterone increased the proliferation of IBEP-I and -3 cell lines. S.C. injection of the 3 IBEP cell lines into nude mice resulted in the growth of solid tumors between 11 and 16 weeks after inoculation. These cell lines could thus be new models for studying various aspects of the biology and the tumorigenicity of breast-cancer cells. A major interest of these new cell lines is that 2 of them were ER- and PgR+, which is an exceptional phenotypic feature. These 2 cell lines could be interesting models for studying the regulation of PgR and the effects of progestins and antiprogestins independently of the presence of ER.

Aged↗
PubMed1995

[Immunohistochemical detection of epidermal growth factor receptor (EGF-R) in paraffin sections of breast carcinoma tissue: correlation and clinical significance].

Analyses of the level of expression of the epidermal growth factor receptor (EGF-R) of breast cancer tumours may add independent information about the prognosis for individual patients. Furthermore, the use of monoclonal antibodies directed against EGF-R as therapeutic tools (e.g., Mab 425) requires a reliable evaluation of the individual EGF-R content. Various analytical methods have been published, including (1) biochemical detectonn of EGF-R by a radiolabelled physiological ligand, (125I)EGF, (2) enzymatic analyses of EGF-R content (IEMA), (3) immunological analyses of EGF-R content with a monoclonal antibody (ELISA), and (4) immunohistochemical EGF-R detection. Studies with immunohistochemical analyses of EGF-R overexpression in formalin-fixed, paraffin-embedded tumour samples are rare. In a retrospective study, we examined the clinical data from 142 patients and the EGF-R expression in their formalin-fixed, paraffin-embedded tumour samples. The average follow-up was 69 months. EGF-R expression was compared to oestrogen (ER) and progesterone (PgR) receptor expression, histological grade, tumour size, lymph node metastases and menopause. 52 of 142 tumours were EGF-R positive. EGF-R overexpression correlated with high tumour grade, large tumours and elevated numbers of lymph node metastases. There was no significant correlation between ER or PgR and EGF-R expression. Determination of EGF-R overexpression revealed no significant difference in disease-free interval (DFI) or overall survival (OS). In this study, the determination of EGF-R in formalin-fixed, paraffin-embedded tumour samples proved feasible. Unfortunately, this did not add any additional information concerning DFI or OS.

Adult↗
PubMed2003

Significance of hormone receptor status and tumor vessels in normal, hyperplastic and neoplastic endometrium.

The aims of this study were to identity the roles of tumor vessels and hormone receptor status in normal, hyperplastic, and neoplastic endometrium, and to explore their relationships with other prognostic factors of endometrial adenocarcinoma. Endometrial curettage specimens of proliferative phase and secretory phase endometrium, simple hyperplasia with or without atypia, complex hyperplasia with or without atypia, and grade 1 adenocarcinoma were examined for estrogen receptor alpha (ER alpha), progesterone receptor (PgR), Ki-67 labeling index (LI), cyclin D1, microvessel density (MVD), and area of venules (AV) using an immunoperoxidase method. The results showed high levels of ER alpha in complex hyperplasia, and high levels of PgR in simple hyperplasia without atypia. Expression of ER alpha in the endometrium decreased in a stepwise manner from complex hyperplasia without atypia to grade 1 adenocarcinoma. Expression of PgR in the endometrium decreased in a stepwise manner from simple hyperplasia without atypia to grade 1 adenocarcinoma. In contrast, the expressions of Ki-67 LI, cyclin D1, MVD and AV in the endometrium increased in a stepwise manner from normal, simple or complex hyperplasia with or without atypia to grade 1 adenocarcinoma. These changes may become irreversible on progression from simple or complex hyperplasia to neoplasia.

Adenocarcinoma↗
PubMed2005

Estrogen regulates transcription of the ovine oxytocin receptor gene through GC-rich SP1 promoter elements.

Establishment of pregnancy in ruminants results from paracrine signaling by interferon tau (IFNT) from the conceptus to uterine endometrial luminal epithelia (LE) that prevents release of luteolytic prostaglandin F(2alpha) pulses. In cyclic and pregnant ewes, progesterone down-regulates progesterone receptor (PGR) gene expression in LE. In cyclic ewes, loss of PGR allows for increases in estrogen receptor alpha (ESR1) and then oxytocin receptor (OXTR) gene expression followed by oxytocin-induced prostaglandin F(2alpha) pulses. In pregnant ewes, IFNT inhibits transcription of the ESR1 gene, which presumably inhibits OXTR gene transcription. Alternatively, IFNT may directly inhibit OXTR gene transcription. The 5' promoter/enhancer region of the ovine OXTR gene was cloned and found to contain predicted binding sites for activator protein 1, SP1, and PGR, but not for ESR1. Deletion analysis showed that the basal promoter activity was dependent on the region from -144 to -4 bp that contained only SP1 sites. IFNT did not affect activity of the OXTR promoter. In cells transfected with ESR1, E2, and ICI 182,780 increased promoter activity due to GC-rich SP1 binding sites at positions -104 and -64. Mutation analyses showed that the proximal SP1 sites mediated ESR1 action as well as basal activity of the promoter. In response to progesterone, progesterone receptor B also increased OXTR promoter activity. SP1 protein was constitutively expressed and abundant in the LE of the ovine uterus. These results support the hypothesis that the antiluteolytic effects of IFNT are mediated by direct inhibition or silencing of ESR1 gene transcription, thereby precluding ESR1/SP1 from stimulating OXTR gene transcription.

Animals↗
PubMed2000

[The analysis of estrogen and pregesterone receptors in leiomyomas cell in different phases of menstrual cycle].

The aim of a study was immunocytochemical analysis of estrogen (ER) and progesterone (PgR) receptors in uterine leiomyomas cells derived from patients who underwent an operation in three different phases: in the follicular phase of the menstrual cycle (12 cases), in the luteal phase (20 cases) and in the postmenopausal age (18 cases). The examined receptors reflect the tissue sensibility to activity of sex steroid hormones and play an important role in the pathogenesis of uterine leiomyomas. Performed studies showed that expression of ER and PgR does not depend on the phase of the menstrual cycle and that it seems to be similar like in the postmenopausal stage. In all groups PgR expression was significantly higher then the expression of ER. In the group of patients in which the surgery was performed during the luteal phase of the menstrual cycle was demonstrated negatively correlation (-0.4846) between the expression of ER in relation to the expression of PgR.

Female↗
PubMed1998

Predicted anti-oestrogen resistance in BRCA-associated familial breast cancers.

There is controversy concerning the prognosis of breast cancers arising in women carrying loss of function mutations in the breast cancer susceptibility genes BRCA1 and BRCA2. This study was carried out to assess the likely hormone dependence of this group of tumours in comparison with an age and grade matched group of control sporadic tumours. We used quantitative immunohistochemical analysis for the oestrogen receptor (ER), progesterone receptor (PgR), cyclin D1 and pS2 on sections of primary tumours and ductal carcinoma in situ (DCIS). Expression of PgR (P < 0.05) and cyclin D1 (P < 0.01) was low in the BRCA1- and BRCA2-associated cancers compared with sporadic cases. The low frequency of expression of ER (9/40), PgR (2/40) cyclin D1 (5/36) and pS2 (5/36) in the familial tumours indicates that the majority of such tumours will be oestrogen insensitive and unlikely to respond to hormonal manipulation even at the in situ stage in their evolution. The low level of PgR (2/40 cases) suggests that there may be some abnormality of transactivating function of the ER in these tumours.

Adult↗
PubMed2006

Recombinant human follicle-stimulating hormone alters maternal ovarian hormone concentrations and the uterus and perturbs fetal development in mice.

Gonadotropins are routinely administered to produce multiple oocytes for clinical in vitro fertilization (IVF) treatment, laboratory research, and livestock industries. Studies in mice have shown gonadotropin stimulation using equine chorionic gonadotropin (eCG) affects the endometrium, implantation, and fetal development. Evidence from clinical studies also indicates that stimulation with recombinant human follicle-stimulating hormone (rhFSH) may be detrimental to the endometrium and implantation rates. We investigated the effect of rhFSH in mice on maternal plasma hormone concentrations and uterine gene and protein expression and the effect of a stimulated maternal environment on pregnancy. Adult females were stimulated with rhFSH or eCG, followed by human chorionic gonadotropin (hCG). On day 4 of pseudopregnancy, mice either had embryos transferred to the uterus or were killed, and blood and uterine samples were collected. Pregnancy outcomes were examined on day 15. Gonadotropin stimulation increased plasma progesterone concentrations on day 4 compared with controls, whereas estradiol concentrations were unaffected. Stimulation also reduced uterine leukemia inhibitory factor (Lif) mRNA, but the expression of estrogen and progesterone receptors (Esr1 and Pgr), homeobox gene Hoxa10, and Vegf mRNA were unchanged. Furthermore, distribution of uterine PGR protein expression was altered by stimulation, but LIF protein was unchanged. Stimulated embryo transfer recipients had lower pregnancy rates than controls, and fetuses from the rhFSH group had reduced weight, length, and maturity. These results demonstrate that gonadotropin stimulation with rhFSH or eCG alters the preimplantation maternal environment, which results in reduced pregnancy rates and fetal development in the mouse.

Animals↗
PubMed1999

Biological markers as indicators of response to primary and adjuvant chemotherapy in breast cancer.

Interest in translational studies on breast cancer is presently devoted to identify biological predictors of treatment response. In patients with operable breast cancer, subjected to primary and adjuvant chemotherapy, we analyzed the predictivity on objective clinical response and relapse-free survival of biological markers related to different cellular aspects and functions. Tumour proliferative rate (evaluated as the (3)H-thymidine-labelling index, TLI), oestrogen and progesterone receptors (ER and PgR, evaluated by the dextran-coated-charcoal method), nuclear DNA ploidy and the immunocytochemical expression of p53, bcl-2 and bax proteins were determined before primary treatment, at the time of diagnosis, and after primary chemotherapy, at surgery. Objective clinical response was significantly related only to pre-treatment p53 expression or PgR status, with a higher rate for tumours not expressing than for those expressing p53 (94% vs. 72%), as well as for PgR-negative (PgR(-)) than for PgR-positive (PgR(+)) tumours (86% vs. 68%). In the overall series, 8-year clinical outcome was significantly related only to post-treatment steroid receptors. In particular, higher 8-year relapse-free survival rate was observed for patients with ER(-) or PgR(-) than for those with ER(+) (64% vs. 38%) or PgR(+) (53% vs. 37%) tumours. Such findings held true even within the sub-set of patients who received adjuvant post-operative chemotherapy, i.e., those with node-positive (N(+)) or ER(-)/node-negative (N(-)) tumours, among whom also rapid proliferation or the presence of apoptosis-favouring markers (bcl-2(-) or bax(+), singly and in association) on surgical specimens identified a sub-set of women who benefited from systemic treatment. The different biological markers were variously indicative of clinical outcome, with a predictivity on tumour shrinkage for p53 and PgR, detected before primary chemotherapy, and on long-term follow-up for ER, PgR and, to a lesser extent, TLI and apoptosis-modulating markers. Int. J. Cancer (Pred. Oncol.) 84:580-586, 1999.

Apoptosis↗
PubMed1995

Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer.

Changes in estrogen receptor (ER) expression and function may explain the development of tamoxifen resistance in breast cancer. ER expression was measured by an immunohistochemical assay, validated for use in tamoxifen-treated tumors against a biochemical enzyme immunoassay, in 72 paired biopsies taken before treatment and at progression or relapse on tamoxifen. Progesterone receptor (PgR) and pS2 gene expression were also measured immunohistochemically as an indicator of ER function. Overall the frequency of ER expression was reduced from 37 of 72 (51%) pretamoxifen to 21 of 72 (29%) at progression or relapse, with a significant reduction in the quantitative level of ER (P < 0.0001; Wilcoxon signed rank sum test). Tumors treated with primary tamoxifen that responded but then developed acquired resistance frequently remained ER positive (ER+) at relapse: 16 of 18 (89%) were ER+ pretamoxifen (75% of these expressed either PgR or pS2) and 11 of 18 (61%) were ER+ at relapse (82% continued to express PgR or pS2). In contrast, only 3 of 20 (15%) tumors that progressed on primary tamoxifen with de novo resistance were ER+ pretamoxifen, and all tumors were ER- at progression. At progression, 6 of 20 (30%) of these tumors expressed high levels of PgR (mean H-score, 98) and/or pS2 (mean, 50% cells positive), despite being ER-. In tumors that recurred during adjuvant tamoxifen therapy, including locoregional and metastatic lesions, ER expression was significantly reduced from 18 of 34 (53%) in the original primary tumor to 10 of 34 (29%) at relapse (P = 0.002). PgR expression was likewise significantly reduced in this group (P = 0.001). This study confirms that expression of a functional ER in breast cancer is a strong predictor for primary response to tamoxifen. Although ER was reduced in tamoxifen-resistant tumors overall, the development of acquired resistance was associated with maintained ER expression and function in many tumors, whereas de novo resistance remained related to lack of ER expression. Recurrence during adjuvant tamoxifen was associated with development of an ER/PgR-negative phenotype in some tumors. These data imply that separate mechanisms of resistance may occur in these different clinical subgroups.

Aged↗
PubMed1999

Pattern of distribution of cells positive for estrogen receptor alpha and progesterone receptor in relation to proliferating cells in the mammary gland.

Since cell proliferation is indispensable for the growth and development of the breast, and estrogens are considered to play a major role in promoting cell proliferation, while progesterone influences its differentiation, the present work was designed with the purpose of verifying the relationship between cells containing steroid hormone receptors and proliferating cells in the normal human breast. Twelve breast samples were analyzed for their content of lobules type 1 (Lob1), Lob2, Lob3, and Lob4, and the number of cells containing estrogen receptor alpha (ER-alpha), progesterone receptor (PgR), or expressing Ki67 antibody was determined by double immunocytochemical technique with specific antibodies. The highest percentage of ER-alpha, PgR, and Ki67 positive cells was found in Lob1, with a progressive reduction in the more differentiated Lob2 and Lob3. ER-alpha and PgR positive cells were found exclusively in the breast epithelium and were negative for Ki67, while cells positive for Ki67 did not express receptors. These findings were compared with the distribution of ER-alpha and PgR in the autoradiographs of mammary gland of young virgin rats inoculated with 3H-thymidine for determination of the DNA labeling index (DNA-LI). Both the DNA-LI and the percentage of ER-alpha and PgR positive cells were maximal in the epithelium of terminal end buds, and these values were reduced in alveolar buds and lobules. ER-alpha and PgR positive cells did not proliferate, and those cells that had incorporated 3H-thymidine were negative for both receptors. Our results led us to conclude that the content of ER-alpha and PgR in the normal mammary tissue varies with the degree of lobular development, in parallel with cell proliferation. However, the expression of receptors occurs in cells other than the proliferating cells, indicating that they represent at least two separate cell populations. These findings open new avenues towards the understanding of the mechanisms through which estrogens and progesterone affect the proliferative activity of breast epithelial cells, and their role in the initiation of the cascade of events that leads a normal cell to cancer.

Adolescent↗