Progesterone Signaling and Mammary Gland Morphogenesis

Progesterone was identified as a mammogenichormone several years ago but until now its precise rolein mammary development has remained obscure. Recentlywith the generation of several transgenic mouse models and development of reagents for analysisof progesterone receptor expression, the role ofprogesterone signaling in mammary development isbecoming more clear. The most significant observationsto emerge from these studies are (1) progesteronereceptors (PR)4 are present in a heterogeneous manner inthe epithelial cells and undetectable in the surroundingfat pad; (2) they are essential for lobuloalveolar and not for ductal morphogenesis; (3)progesterone signaling through progesterone receptors,leading to lobuloalveolar development, is initiated inthe epithelium and may occur through paracrinemechanisms; and (4) a regulated expression of the twoisoforms of progesterone receptor is critical formaintaining appropriate responsiveness to progesteroneand hence, epithelial cell replicative homeostasis.These studies also reveal that the consequences ofprogesterone signaling through progesterone receptor maydepend on the cell context, cell-cell andcell-extracellular matrix interactions, the dynamics ofPR turnover and the fate of PR positivecells.     

人精子质膜孕激素受体研究

目的 :观察人精子表面孕激素受体 (PR)的定位及阳性表达率。　方法 :精子体外获能后 ,应用异硫氰酸荧光素标记的牛血清白蛋白 孕酮复合物 (P BSA FITC)染色 ,荧光显微镜观察及流式细胞术 (FCM )定量分析法 ,分别观察与孕酮 (P)结合精子形态及标记精子所占比例。　结果 :P BSA FITC染色精子的形态主要表现为 2种类型 :整个顶体区域或仅赤道区呈绿色荧光 ,顶体后区及尾部不着色。与P结合精子的百分率为 (30 2± 2 4 ) %。　结论 :人精子顶体表面有PR表达 ,且这种表达呈选择性     

Correlation between sex hormone binding and peritumoral edema in intracranial meningiomas

Estrogen and progesterone receptor binding activity was measured in 22 intracranial meningioma surgical specimens. None of the tumors was estrogen receptor-positive, whereas 19 were progesterone receptor-positive. Of these 19 patients, all demonstrated significant computed tomographic (CT) evidence of peritumoral edema. None of the 3 patients who lacked progesterone receptor binding had CT evidence of peritumoral edema (P less than 0.005). Peritumoral edema associated with intracranial meningiomas seems to be related, at least in part, to progesterone binding activity. This implicates the potential use of progesterone antagonists for the treatment of incompletely resected or recurrent meningiomas.     

Quantitative Progesterone Receptor Expression and Efficacy of Anti‐estrogen Therapy in Breast Cancer

The central role of estrogen receptor (ER) presence in predicting which breast cancer patients are likely to benefit from anti‐estrogen therapies is well‐established, but the added benefit of progesterone receptor (PR) and in particular low levels of PR is less well understood. The objective of this study was to determine the quantitative relationship between borderline levels of PR and subsequent benefit from anti‐estrogen therapy. We examined data from 447 patients, age 50 or older. ER and PR levels were quantitated by conventional ligand binding assay and Scatchard plot analysis or by enzyme‐linked immunoassay. Comparison of clinical outcome in relation with ER and PR status was calculated using Kaplan‐Meier actuarial survival analysis and the log‐rank test. Subpopulation treatment effect pattern plot (STEPP) analysis was used to explore the interaction between treatment effects and ER or PR levels for the 409 patients with ER values greater than 0. For anti‐estrogen treated patients, when the ER and PR positivity cut‐off was set at 1.0 fmole/mg protein, there was a statistically significant advantage for patients with ER+PR+ over ER+ PR? tumors for both breast cancer‐free interval (BCFI) and overall survival (OS). STEPP analysis found no overall interaction between treatment outcome (5 year survival probability) and levels of hormone receptor. However, patients with borderline PR levels did not appear to benefit from anti‐estrogen therapy. PR levels above borderline in addition to the presence of ER predicts an increased probability of benefit from anti‐estrogen therapy in breast cancer patients.     

Estrogen and progesterone receptors in meningiomas: comparison of nuclear binding, dextran-coated charcoal, and immunoperoxidase staining assays

We studied the status of estrogen (ER) and progesterone (PR) receptors in meningiomas removed from 52 patients, comparing dextran-coated charcoal (DCC), nuclear binding (NB), and immunoperoxidase (IP) assays. Each of the assays was performed independently by investigators well-experienced with these assays. The NB assay is a new assay that measures functional steroid receptors--that is, the activation of the receptor and its binding to the nucleus. The assay is very sensitive and requires a relatively small amount of tissue as compared with the DCC assay. In agreement with data from other studies. PR were detected in most meningiomas by all 3 methods: in 69% of the cases by NB, in 76% by DCC, and in 89% by IP. ER were detected in only a few cases: in 33% by NB, in 2% by DCC, and in none by the IP assay. The agreement for PR sites was 62% for all 3 assays; it was 66% between the NB and DCC assays, 67% between the NB and IP assays, and 86% between the DCC and IP assays. Of 26 cases that were positive by the DCC assay, 6 (23%) were negative by NB. The overall agreement for all three ER assays was 65%. The data suggest that the majority of meningiomas contain high-affinity receptors for progesterone, that estrogen receptors are present in only a few meningiomas, and that some of these estrogen and progesterone receptors appear to be functional.     

85例青年乳腺癌临床病理特点及预后的回顾性分析

【摘要】 目的 回顾性研究85例青年乳腺癌的临床病理特点,探讨青年乳腺癌的临床病理特点,并分析其对临床预后的影响。方法〓本研究将收治的青年乳腺癌(≦35岁)85例作为青年组,将同时期收治的中老年乳腺癌(﹥35岁)98例作为中老年组,收集其临床病理类型,包括雌激素受体(ER)和孕激素受体(PR)、Her-2表达、P53表达方面、腋窝淋巴结转移情况和术后5年无病生存率等方面开展比较,进行统计学分析。结果〓青年组乳腺癌和中老年组乳腺癌在病理类型上、组织学分级及临床分期上均无显著差异(P>0.05);在ER、PR及Her-2的表达方面具有显著差异(P<0.05);而在P53的表达方面无显著差异(P>0.05);在腋窝淋巴结转移率方面具有显著差异(P<0.05);两组在术后5年无病生存率上的差异具有统计学意义(P<0.05)。结论〓青年乳腺癌的病理类型提示其较中老年乳腺癌有更强的侵袭性,淋巴结转移较早,5年无病生存率较低,所以在临床上改善其预后最好的办法是早期发现并早期接受规范化治疗。     

Correlations of female steroid hormone receptors with histologic features in meningiomas

Summary A series of 39 samples were obtained from meningiomas in 28 patients in order to investigate the relationships of the oestrogen receptor (OER) and progesterone receptor (PR) with the tumoural subtype and some histological features. Twenty-one samples were positive (> 10 fmole/mg protein), 7 were OER-PR-negative, and 1 was positive in both receptors. Twenty-two samples were considered as syncitial, 7 transitional, 7 fibroblastic and 3 angioblastic. The histological subtype was not found to be significantly related to the presence or absence of PR. Relations were not observed between the progestin receptor and the following histological parametrs: cellular pattern, cell density, nuclear polymorphism, mitosis, lymphoplasmacellular infiltrates, degree of vascularization, psammoma bodies and interstitial fibrosis. Only the presence of intratumoural necrosis was significantly related with a low PR levels. However, progesterone binding activity was lower in tumours with numerous psammomas, fibroblastic cell pattern and interstitial fibrosis. The clinical and biological significance of these results is discussed.     

The Loss of Estrogen and Progesterone Receptor Gene Expression in Human Breast Cancer

Hormone responsiveness is a critical determinantof breast cancer progression and management, and theresponse to endocrine therapy is highly correlated withthe estrogen receptor (ER)³ and progesterone receptor (PR) status of tumor cells. Thus, keyareas of study in breast cancer are those mechanismsthat regulate ER and PR expression in normal andmalignant breast tissues. One-third of all breastcancers lack ER and PR; these conditions are associatedwith less differentiated tumors and poorer clinicaloutcome. In addition, approximately one-half ofER-positive tumors lack PR protein and patients withthis phenotype are less likely to respond tohormonal therapies than those whose tumors express bothreceptors. Since PR is induced by ER; its presence is amarker of a functional ER. In this review, we will discuss possible mechanisms for loss of ER andPR gene expression, especially structural changes withineach gene including deletions, polymorphisms ormethylation. Improved understanding of the pathways that lead to loss of ER and/or PR proteinsshould allow the development of better predictiveindicators as well as novel therapeutic approaches totarget these hormone-independent cancers.     

ER−/PR+/HER2− breast cancer type shows the highest proliferative activity among all other combined phenotypes and is more common in young patients: Experience with 6643 breast cancer cases

The characterization of breast cancer according to its proliferative activity and the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor‐2 is a laboratory routine that has been adopted worldwide for prognostic and therapeutic purposes. By combining data on the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor‐2, it is possible to obtain 8 tumor patterns categorized as triple‐negative, nonluminal (i.e. positive for human epidermal growth factor receptor‐2 with four subtypes) and luminal (negative for human epidermal growth factor receptor‐2 and positive for estrogen receptor and/or progesterone receptor with three subtypes) tumors. In general, luminal tumors are associated with a higher degree of tumor differentiation and have more favorable clinical outcomes. One of the subtypes of luminal tumors has an ER?/PR+ profile. This is a rather rare tumor subtype that behaves aggressively. The aim of this work was to analyse the proliferative activity of the eight tumor subgroups to verify if the ER?/PR+ type has a higher proliferative activity than the other subtypes, which might be correlated with its more aggressive behavior. To accomplish this, we examined estrogen receptor, progesterone receptor, human epidermal growth factor receptor‐2 and Ki67 data from 6643 cases of breast cancer. We found that the tumor type that was positive for only the progesterone receptor and negative for both the estrogen receptor and human epidermal growth factor receptor‐2 (1.3% of all cases) had a proliferative activity that was consistently much higher than those of the other luminal subtypes.     

Roles of hormone replacement therapy and iron in proliferation of breast epithelial cells with different estrogen and progesterone receptor status

Estrogen and iron play critical roles in a female body development and were investigated in the present study in relation to in vitro cell proliferation. Prempro, a hormone replacement therapy drug, and 17beta-estradiol (E2) were shown to increase cell proliferations in estrogen receptor positive (ER+) cells independent of progesterone receptor (PR) status. For example, increased cell proliferation was observed in ER+/PR+ human breast cancer MCF-7, its matching non-cancerous human breast epithelial MCF-12A, and ER+/PR+ murine mammary cancer MXT+ cells, but not in ER-/PR- MDA-MB-231, its matching non-cancerous MCF-10A, and MXT- (ER-/PR+) cells. By mimicking post-menopausal conditions of high estrogen in local breast tissue and increased iron levels due to cessation of menstrual periods, E2 and iron were shown to exert synergistic effects on proliferation of MCF-7 cells and significantly increased Ki67 and proliferating cell nuclear antigen. Western blotting of E2-treated ER+ but not ER- cells showed that E2 also increased transferrin receptor (TfR). Further studies are needed to assess the mitogenic effects of iron and estrogen in normal post-menopausal breast.     

Differences in the Progesterone Receptor Contents Between Familial Breast Cancers and Sporadic Breast Cancers Stratified by Patient Age

In the present study, we investigated the estrogen (ER) and progesterone receptor (PR) contents of familial breast cancers (FBCs) and compared the findings with those of sporadic breast cancers, stratified by the patients' age. To evaluate the hormone receptor contents of Japanese FBCs, we collected a consecutive series of 250 FBCs and 2533 sporadic breast cancers (SBCs). These patients were divided into the three groups stratified by the patients' age at initial surgery (group I, under 40 years old; group II, 40–60 years old; group III, over 60 years old). The clinicopathological features of FBCs and SBCs, including ERs and PRs, were analyzed for each group. In all age groups, the PR contents of FBCs were significantly lower than those of SBCs, particularly for group III. In FBCs, the PR content was significantly lower in group III than in groups I or II. In addition, there was a nonsignificant trend towards a high frequency of ER-positive, PR-negative tumors in FBC patients aged 60 years and over. These data indicate that the loss of ER function and/or loss of binding capacity of PR to progesterone was associated with some late-onset FBCS. Received: February 13, 2001 / Accepted: July 17, 2001     

Role of the Androgen Receptor in Human Breast Cancer

Although the androgen receptor (AR)³is often co-expressed with the estrogen receptor (ER)and progesterone receptor (PR) in human breast tumors,its role in breast cancer is poorly understood. Specific growth stimulatory and inhibitory actions ofandrogens have been described in human breast cancercell lines. The mechanisms by which androgens exertthese contrasting growth effects are unknown. A commonly utilized second line therapy for the treatmentof advanced breast cancer is high dosemedroxyprogesterone acetate (MPA). Although MPA, asynthetic progestin, was thought to act exclusivelythrough the PR, the androgenic side-effects observed in womentaking MPA suggest that its action may also be mediatedin part by the AR. In support of this hypothesis, thelevel of AR measured by radioligand binding in primary breast tumors was correlated with theduration of response to MPA treatment following failureof tamoxifen therapy. Recent data suggest that thepresence of structurally altered AR in breast cancers may account for unresponsiveness to MPA in someof these cases. Further studies are warranted todetermine the role of AR mediated pathways in regulatingbreast tumor growth. In particular, identification of androgen-regulated genes may lead to newpossibilities for the hormonal treatment of breastcancer.     

Estrogen receptor immunoreactivity in meningiomas. Comparison with the binding activity of estrogen, progesterone, and androgen receptors

Estrogen receptor (ER) analysis was performed in 70 meningioma samples by means of two assays: an enzyme immunoassay that used monoclonal antibodies against human ER protein (estrophilin), and a sensitive radioligand binding assay that used iodine-125-labeled estradiol as the radioligand. Low levels of ER immunoreactivity were found in tumors from 51% of patients, whereas ER binding activity was demonstrated in 40% of the meningiomas examined. In eight (11%) of the tissue samples, multiple binding sites for estradiol were observed. The immunoreactive binding sites corresponded to those of the classic high-affinity ER. In ligand binding studies, however, measurement of classic ER was considerably influenced by a second low-affinity high-capacity estrogen binding component, even at low ligand concentrations. Binding activity of the progesterone receptor (PR) and androgen receptor (AR) was determined concurrently using 17 alpha-methyl-3H-promegestone (3H-R 5020) and 17 alpha-methyl-3H-trienolone (3H-R 1881), a synthetic gestagen and androgen, respectively. High concentrations of PR were detected in 53 (76%) of the tumors, whereas a moderate number of AR binding sites were demonstrated in 33 (47%) of the tumors. A positive correlation between ER immunoreactivity and AR binding activity is suggestive of estrogen regulation of AR via the ER system. The presence of gonadal steroid receptors in a large proportion of meningiomas and the tendency toward a dependence of receptor concentrations on the histological subtype of the meningioma could have implications for tumor therapy.     

The effects of ischemia on estrogen and progesterone receptor profiles in the rodent uterus

Ischemia is considered to invalidate the estrogen receptor (ER) and progesterone receptor (PR) values of tissues available for steroid hormonal analysis. To evaluate the temporal effect of devascularization on steroid receptors, complete uterine ischemia was induced in vivo in 64 female Buffalo rats (80-154 g). Animals were assigned to varying intervals of ischemia (0-90 min) and were maintained at a constant ambient (75 degrees F) and core-body temperature (100-102 degrees F). Following tissue preservation at -80 degrees C, multipoint titration of steroid binding capacity (SBC) was performed with [3H]estradiol 17-beta (3-0.15 nM) or [3H] R5020 (8-0.4 nM) in the presence or absence of a 200-fold excess of an unlabeled ligand. Applying nonlinear regression analysis, ischemia was observed to decrease the binding capacitance for both ER and PR profiles of rodent uterine tissues at 30 min with significant decay over the 90-min interval of devascularization (ER, P less than 0.01; PR, P less than 0.1). Significant reduction in SBC was evident after 80 min of ischemia for PR (P less than 0.05) and 90 min of tissue ischemia for ER (P less than 0.05) comparative to control (t0) valves. The detrimental effect of progressive ischemia on ER and PR values was such that it appears essential to assure rapid and reliable tissue aliquot preservation techniques when organ ischemia greater than or equal to 90 min is anticipated.     

Expression of estrogen receptor alpha and progesterone receptor in children with undescended testicle previously treated with human chorionic gonadotropin

PURPOSE: The aim of this study was to investigate expression of estrogen receptor alpha (ERalpha) and progesterone receptor (PR) in paratesticular tissues obtained from boys with undescended testes. MATERIALS AND METHODS: A total of 65 boys with unilateral cryptorchidism and failed human chorionic gonadotropion treatment underwent orchiopexy. A small sample of gubernaculum, cremasteric muscle and processus vaginalis was obtained. A total of 57 boys who underwent inguinal hernia repair served as the control group. All boys in the control group had testes in the scrotum. The expression of estrogen receptor alpha and progesterone receptor was measured by counting the number of ERalpha or PR positive cells detected by immunohistochemical analysis. RESULTS: ERalpha and PR density was higher in cremasteric muscle and processus vaginalis obtained from boys with undescended testes than in the control group. Density of progesterone receptor in the examined groups was lower than the density of estrogen receptor. CONCLUSIONS: ERalpha and PR are expressed in paratesticular tissues important for normal testicular descent. ERalpha was over expressed in cremasteric muscle and processus vaginalis in boys with undescended testes previously treated with human chorionic gonadotropin.     

Understanding the biologic mechanisms responsible for breast-cancer progression during tamoxifen or fulvestrant treatment

BACKGROUND: Dehydroepiandosterone sulfate (DHEAS) causes breast-cancer proliferation, even during tamoxifen or fulvestrant blockade. The purpose of this study was to determine possible mechanisms for this treatment failure. METHODS: T-47D cells (estrogen receptor [ER] and progesterone receptor [PR] positive) were treated with fulvestrant (10 micromol/L), tamoxifen (10 mmol/L or 0.0001 nmol/L), or vehicle and stimulated with DHEAS. Gene expression of ER, PR, insulin-like growth factor (IGF)-1 and -2, and insulin-like growth-factor binding protein (IGFBP)-1 through -4 was determined. RESULTS: ER and PR gene expression decreased by 1.3- and 4-fold with fulvestrant and DHEAS. ER expression decreased by 2.7-fold with 0.0001 nmol/L tamoxifen and DHEAS. ER and PR expression were unchanged by 10 nmol/L tamoxifen. IGF-1 and IGF-2 were not expressed. IGFBP-2 and -4 expression decreased by 1.9- and 1.6-fold after DHEAS stimulus, although this was not statistically significant. CONCLUSIONS: DHEAS exposure, even in the presence of tamoxifen and fulvestrant, induces changes in ER and PR gene expression that may be partially responsible for breast cancer progression.     

前列腺带性结构及其雄激素、雌激素、表皮生长因子受体分布特征的研究

为了探讨雄激素受体（ＡＲ）、雌激素受体（ＥＲ）、孕激素受体（ＰＲ）和表皮生长因子受体（ＥＧＦＲ）在前列腺带性结构中的分布，应用单饱和剂量测定法，分别测定了前列腺移行带、外周带组织中ＡＲ、ＥＲ、ＰＲ和ＥＧＦＲ的含量。结果表明，在１１例前列腺增生症（ＢＰＨ）患者２２份标本中，移行带和周围带ＡＲ全部阳性；尽管ＡＲ浓度个体差异很大，但是两带之间仍有密切相关性（Ｐ＜０００１）；周围带ＡＲ浓度高于移行带，两带ＡＲ浓度均高于ＰＲ、ＥＲ；ＰＲ和ＥＲ在前列腺带性结构上没有明显差异。ＥＧＦＲ在移行带明显高于周围带。研究证实了ＡＲ、ＥＲ、ＰＲ，ＥＧＦＲ在前列腺移行带和周围带上的分布特征。     

Steroid hormone and epidermal growth factor receptors in meningiomas

A prospective study of steroid hormone and epidermal growth factor receptor expression in 57 meningiomas is presented. Scatchard analysis of radioligand binding identified 20% of meningiomas as expressing classical oestrogen receptors (ER) at levels below that normally accepted for positivity, the remainder being negative. ER could not be visualized in any meningioma using immunocytochemistry. Alternatively, 74% of meningiomas demonstrated the presence of progesterone receptors (PR) by Scatchard analysis, the specificity of which could not be attributed to glucocorticoid or androgen receptors. Confirmation of classical PR presence was determined by immunocytochemical staining. The presence of epidermal growth factor receptor (EGFR) was demonstrated in 100% of meningiomas using immunocytochemical staining. These data are reviewed in the context of previously reported results and are discussed in relation to the potential for medical therapy as an adjunct to surgery.     

流式细胞计数测定抗孕激素对猪卵巢细胞孕酮受体的影响

为了研究抗孕激素调节卵巢功能的机理 ,制备了人胎盘羊膜的双池培养系统。分离猪卵巢颗粒细胞和内泡膜细胞 ,分别种在羊膜两侧。在加入或不加 RU486和ZK98.73 4时 ,两种细胞在促性腺激素刺激下共同培养。 48h后 ,应用流式细胞计数(FCM)测定两种细胞的孕酮受体 (PR)和雌激素受体 (ER) ;放射免疫法测定培养液中的孕酮 (P)和雌二醇 (E2 )浓度。结果显示 ,抗孕激素增加两种细胞的 PR含量 ,ER没有明显改变 ;颗粒细胞的 P和 E2 分泌受到抑制 ,内泡膜细胞的 P分泌也减少。提示 P调节 P本身的合成 ,这种旁分泌和自分泌作用是通过 P控制 PR上调的途径。这可能是抗孕激素对卵泡发育和甾体激素生成功能的抑制机理之一