雌、孕激素受体与子宫内膜癌相关性的研究

目的　通过对雌、孕激素受体表达水平的检测分析 ,探讨雌、孕激素受体的表达水平与子宫内膜癌的发生、发展的关系。方法　收集我科经手术治疗的新鲜活体组织标本 ,并经病理组织学确诊的子宫内膜癌 30例。采用较新的LSAB免疫组织化学方法检测雌激素受体 (ER)和孕激素受体 (PR)的表达水平。结果　ER和PR的阳性率一致 ,均为 6 6 6 7% :组织学分级高分化腺癌 (Ⅰ级 )的阳性率为 4 0 % ,明显高于中、低分化者 (Ⅱ、Ⅲ级 ) ;临床分期早期 (Ⅰ期 )的阳性率为 4 3 33% ,明显高于中、晚期 (Ⅱ、Ⅲ期 )患者 (P <0 0 1)。在同一标本不同部位的癌灶、癌旁和正常组织中ER和PR的阳性率显示癌灶组织明显低于癌旁和正常组织(P <0 0 5 )。结论　ER和PR的表达水平与子宫内膜癌的组织学分级和临床分期有一定的关系 ,高分化癌的ER和PR表达水平高 ,低分化癌的ER和PR含量低 ;临床分期早期患者的ER和PR含量高 ,中、晚期患者的ER和PR含量低。笔者认为 :ER和PR的检测对子宫内膜癌的组织学分化趋势、分级及临床分期和内分泌治疗与对预后的监测有指导意义     

雌激素受体和孕激素受体在葡萄胎中的表达和意义

目的：探讨雌激素受体（estrogen receptor，ER）及孕激素受体（progesterone receptor，PR）在葡萄胎（hydatidiform mole）的表达的临床意义。方法：应用SP法检测30例葡萄胎组织中ER、PR的表达情况，以正常早孕绒毛20例为对照。结果：在正常早孕绒毛、葡萄胎组织中，ER、PR表达均无统计学差异。葡萄胎中ER表达与子宫大小无相关性，与HCG水平、卵巢黄素囊肿直径、重复性葡萄胎未见关联，与年龄负关联，与葡萄胎的恶变倾向负相关（P〈0．05）。葡萄胎中PR阳性表达率与HCG水平、年龄、重复性葡萄胎、子宫增长速度、葡萄胎的恶变倾向未见相关性。结论：ER表达与葡萄胎恶变高危因素年龄、葡萄胎恶变倾向负关联，PR表达与葡萄胎恶变倾向未见相关性，提示ER可能作为提示葡萄胎恶变倾向的重要指标之一。     

Estrogen and progesterone receptor isoforms: clinical significance in breast cancer

The identification and exploitation of biomarkers that may predict response to anti-cancer treatments has the capacity to revolutionize the way that patients with cancer are treated. In breast cancer, the estrogen receptor (ER) and the progesterone receptor (PgR) are known to have a significant predictive value in determining sensitivity to endocrine therapies. Tumor expression of ER or PgR is known to affect clinical outcome and this information is often used to determine a patient's optimal treatment regimen. However, the measurement of ER and PgR alone is more complex than originally thought and the impact of the recently identified isoforms of ER (ERα and ERβ) and PgR (PgRA and PgRB), as well as several variant and mutant forms, upon the choice of treatment remains unclear. Therefore, ER and PgR expression alone are unlikely to determine a patient's optimal treatment regimen, particularly when the amount of ‘cross-talk’ between different pathways, such as the epidermal growth factor receptor pathway, is considered. In order to account for the complex cell-signaling environment that occurs in breast cancer, multifactorial techniques are needed to analyze tumor biomarker expression. The recent advances in genomic- or proteomic-based approaches has enabled molecular portraits of breast cancers to be painted, allowing biomarkers of response and prognosis to be identified and characterized more accurately than before. In the future, patients could be treated according to the molecular portrait of their tumor biomarker expression, maximizing the therapeutic benefit that each patient receives. This revised version was published online in August 2006 with corrections to the Cover Date.     

Role of the progesterone receptor (PR) and the PR isoforms in breast cancer

Known risk factors for breast cancer include overexposure to exogenous or endogenous hormones, namely, estrogen and progesterone. The effects of progesterone acts via two isoforms of the progesterone receptor (PR) termed A (PRA) and B (PRB). There is a single human PR gene with two distinct promoter regions in exon 1 encoding the two isoforms. Studies have shown that in poor prognostic tumors, the ratio between PRA and PRB is altered, with a predominance of PRA and loss of PRB. PRA and PRB regulate different subsets of genes involved in particular functional pathways. Breast tumors that express PR are associated with slow growth, better differentiation, and better overall prognosis in the short term. Both estrogen receptor alpha (ERalpha) and total progesterone receptor (PR) are immunohistochemically measured on breast cancer specimens to help determine those patients who would benefit from hormonal treatment. Depending on the hormone receptor status and the menopausal status of the patient, different treatments are available. Although the value of ERalpha in predicting response to hormone therapy in early breast cancer patients is undisputed, the value of PR is currently under debate. Historically, PR was thought to be a surrogate marker for ER expression; however, it is now known that lack of PR expression can indicate underlying epidermal growth factor receptor signaling or promoter methylation. This has implications for and can dictate hormone therapy responsiveness. Further studies investigating the specific isoforms and their pathways will help to reveal the underlying mechanisms of PR-induced breast tumori-genesis and help in assigning the most appropriate patient-tailored treatment.     

骨肉瘤组织中雌、孕激素受体的表达及临床意义

目的探讨骨肉瘤组织中雌激素受体（ＥＲ）、孕激素受体（ＰＲ）的表达及其与临床特征的关系。方法应用免疫组化改良ＳＰ方法对６５例骨肉瘤蜡块组织进行了ＥＲ、ＰＲ检测。结合临床特点进行统计学分析。所有病人术前均未接受内分泌治疗。结果骨肉瘤中ＥＲ表达的阳性率为４０％（２６／６５）,ＰＲ表达的阳性率为３２３％（２１／６５）;临床无转移,存活时间长之骨肉瘤中ＥＲ、ＰＲ表达的阳性率高于临床有转移、存活时间短者,差异有显著性意义（Ｐ＜００５）;不同性别、年龄、发病部位的骨肉瘤中ＥＲ、ＰＲ表达的阳性率无显著性差异（Ｐ＞００５）。结论骨肉瘤中存在ＥＲ、ＰＲ,ＥＲ、ＰＲ的检测可提示为骨肉瘤生物学行为,对病人预后的评估及探讨骨肉瘤内分泌治疗提供重要的理论依据。     

miR-129-2 mediates down-regulation of progesterone receptor in response to progesterone in breast cancer cells

Objective: Hormonal therapy is an important component of first line of treatment for breast cancer. Response to hormonal therapy is influenced by the progesterone receptor (PR)-status of breast cancer patients. However as an early effect, exposure to progesterone decreases expression of PR in breast cancer cells. An understanding of the mechanism underlying down-regulation of PR could help improve response to hormonal therapy. Methods: We performed small RNA sequencing of breast cancer cells for identification of microRNAs targeting PR in response to progesterone treatment. Biochemical approaches were used to validate the findings in breast cancer cells. Results: Analysis of small RNA sequencing of four breast cancer cell lines treated with progesterone revealed an up-regulation of miR-129-2 independent of the PR status of the cells. We show that miR-129-2 targets 3′UTR of PR to down-regulate its expression. Furthermore, inhibition of miR-129-2 expression rescues the down-regulation of PR in breast cancer cells. Also, the expression levels of miR-129-2 was observed to be elevated in patients with low expression of PR in the TCGA cohort (n = 359). Conclusion: miR-129-2 mediates down-regulation of PR in breast cancer cells in response to progesterone, while anti-miR-129-2 could potentiate PR expression levels among patients with inadequate PR levels. Thus, modulation of activity of miR-129-2 could stabilize PR expression and potentially improve response to hormonal therapy under adjuvant or neo-adjuvant settings.     

Estrogen and progesterone receptor profile patterns in primary breast cancer

Summary Estrogen (ER) and progesterone receptor (PgR) analyses have been performed in 884 primary, malignant human breast tumor biopsies. Receptor contents were evaluated with respect to age and menopausal status. The frequency of ER + tumors was found to be significantly higher in postmenopausal than in pre/perimenopausal women. Age rather than menopausal status was found to be associated with this difference. The significant association with age was found in the post- but not the pre/perimenopausal women.The frequency of PgR + tumors was found to be significantly lower in the postmenopausal than in the pre/perimenopausal women. Neither age nor menopausal status alone could account for this difference, which appears to be due to a compound effect of the two factors.The distribution of receptor profile patterns is described according to menopausal status. The patterns differ significantly in pre- and postmenopausal women. PgR dominates in the premenopausal tumor while ER dominates in the postmenopausal tumor. This difference is apparent within the subgroup of ER + PgR + patients as well.The current tenets for prediction of recurrent disease utilizing steroid hormone receptor determinations are discussed for the group of ER + PgR + patients.sponsored by The Danish Cancer Society     

The detection and analysis of estrogen and progesterone receptors in breast cancer (report of 1,393 patients)

Objective To explore the distribution of estrogen receptors (ER) and progesterone receptors (PR) in patients with breast cancer and to compare the results with clinical parameters. Methods Breast cancer specimens of 1393 cases were stained for the ER and PR by a SP Two -Step method, and analyzed with respect to age, menstrual status, histopathology and metastasis of axillary lymph nodes. Results The correlation coefficients between ER and PR were positive-(P< 0.0001). The negative expression of ER in patients 39 years or less was the highest with a statistical significance (P<0.0001 ). There was no relationship between the patient’s age and positive expression of ER, PR and negative expression of PR (P>0.05). There were significantly higher positive rates of ER and lower positive rates of PR in post-menopausaf patients than in pre -menopausal cases(P<0.0001). There was no relationship between the status of ER, PR and the corresponding histopathology (P>0.05). The patients with no metastasis in the axillary lymph nodes had higher simultaneous positive rates of ER and PR (P<0.0001), and those with axillary lymph node metastasis had significantly higher rates of negative expression of ER and PR(P<0.0001). Conclusion The positive and negative distributions of ER and PR have some regular patterns which may be used as a reference to choose combined therapy and to predict the prognosis for breast cancer patients.     

The Detection and Analysis of Estrogen and Progesterone Receptors in Breast Cancer （Report of 1,393 Patients）

Objective  To explore the distribution of estrogen receptors (ER) and progesterone receptors (PR) in patients with breast cancer and to compare the results with clinical parameters. Methods  Breast cancer specimens of 1393 cases were stained for the ER and PR by a SP Two -Step method, and analyzed with respect to age, menstrual status, histopathology and metastasis of axillary lymph nodes. Results  The correlation coefficients between ER and PR were positive-(P< 0.0001). The negative expression of ER in patients 39 years or less was the highest with a statistical significance (P<0.0001 ). There was no relationship between the patient’s age and positive expression of ER, PR and negative expression of PR (P>0.05). There were significantly higher positive rates of ER and lower positive rates of PR in post-menopausaf patients than in pre -menopausal cases(P<0.0001). There was no relationship between the status of ER, PR and the corresponding histopathology (P>0.05). The patients with no metastasis in the axillary lymph nodes had higher simultaneous positive rates of ER and PR (P<0.0001), and those with axillary lymph node metastasis had significantly higher rates of negative expression of ER and PR(P<0.0001). Conclusion  The positive and negative distributions of ER and PR have some regular patterns which may be used as a reference to choose combined therapy and to predict the prognosis for breast cancer patients.     

Cytosol and nuclear estrogen receptors (occupied and unoccupied sites) and progesterone receptors in human breast cancer

Summary Estrogen and progesterone receptor concentrations in cytosol and nucleus were measured in 21 primary breast cancer tumors. Twelve out of the 21 tumor samples were cytosol estrogen receptor positive, 8 of which contained only unoccupied estrogen binding sites in the cytosol, but 2 of the 9 estrogen receptor negative samples did contain cytosol binding sites already occupied by endogenous homone. Four other estrogen receptor negative tumors only showed nuclear binding sites. Only 3 of the 12 estrogen receptor positive tumors also contained progesterone receptors. All of these tumors also had estrogen receptor in the nucleus. However, three of the 17 progesterone receptor negative samples had progesterone receptor only in the nucleus. The present data indicate that 3 possible classes of false negative tumors can be encountered: 1) estrogen receptors occupied by endogenous hormone, 2) tumors containing only nuclear estrogen receptors, and 3) tumors having only nuclear progesterone receptors. Measurement of nuclear estrogen receptor together with the progesterone receptor provides further information on whether the estrogen receptor system is not only present but also functional, and should be of value in the prediction of hormone dependent breast cancer.     

乳腺癌肿瘤组织不同部位雌孕激素受体的表达

目的 探讨乳腺浸润性导管癌肿瘤组织中不同部位雌、孕激素受体表达情况.方法 收集32例手术切除乳腺浸润性导管癌肿瘤标本,于每例肿瘤标本4个不同部位取材,用免疫组化方法检测各部位雌、孕激素受体表达情况.结果 肿瘤组织不同部位雌、孕激素受体检测结果一致性好,最好Kappa值分别为0.789和0.810,最差Kappa值分别为...     

Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease

Cumulative exposure to estrogen (E) and progesterone (P) over the menstrual cycle significantly influences the risk of developing breast cancer. Despite the dogma that PR in the breast merely serves as a marker of an active estrogen receptor (ER), and as an inhibitor of the proliferative actions of E, it is now clear that in the breast P increases proliferation independently of E action. We show here that the progesterone receptor (PR) and ER are expressed in different epithelial populations, and target non-overlapping pathways in the normal human breast. In breast cancer, PR becomes highly correlated with ER, and this convergence is associated with signaling pathways predictive of disease metastasis. These data challenge the established paradigm that ER and PR function co-operatively in normal breast, and have significant implications not only for our understanding of normal breast biology, but also for diagnosis, prognosis and/or treatment options in breast cancer patients.     

Rates for breast cancer characteristics by estrogen and progesterone receptor status in the major racial/ethnic groups

It has been reported that age-specific breast cancer rates vary by estrogen receptor and progesterone receptor status. We report breast cancer rates for age-at-diagnosis, stage-at-diagnosis, histological grade and type by estrogen (ER) and progesterone (PgR) receptor status in six major racial/ethnic groups. The average annual age-adjusted rates for breast cancers with estrogen receptor positive (ER⁺), ER^–, progesterone receptor positive (PgR⁺), PgR^–, ER⁺PgR⁺, ER⁺PgR^–, ER^–PgR⁺ and ER^–PgR^– are determined from 123,732 breast cancers with known ER status, diagnosed from 1992 to 1998 from 11 Surveillance, Epidemiology, and End Results (SEER) cancer registries. For each racial/ethnic group, their ER⁺ (ER⁺PgR⁺ and ER⁺PgR^–) age-specific rates increased with age (but at a slower pace after ages 50–54) while their ER^– (ER^– PgR⁺ and ER^–PgR^–) age-specific rates did not increase after ages 50–54. The rank orders of the rates among the racial/ethnic groups varied by ER/PgR status. The stage I rates were greater than the stage II rates for the ER/PgR groups except for ER^– and ER^–PgR^– cancers. The grade 2 (moderately differentiated) rates were greater than the grades 3 and 4 (poorly differentiated and undifferentiated cancers) rates for ER⁺ cancers, but not for ER^– cancers. These results suggest that although breast cancer is a disease with enormous heterogeneity, the multiple types of breast cancer can be separated into distinct subgroups by their ER status, and perhaps by their ER/PgR status, and their cancer characteristics may be important in understanding the multiple nature of breast cancer.     

Anti-estrogenic mechanism of unliganded progesterone receptor isoform B in breast cancer cells

Over half of breast cancer cases are estrogen-dependent and strategies to combat estrogen-dependent breast cancer have been to either block the activation of estrogen receptor (ER) or diminish the supply of estrogens. Our previous work documented that estrogen-independent expression of progesterone receptor (PR) in MCF-7 cells markedly disrupted the effects of estrogen. In this study, we have developed an adenovirus-mediated gene delivery system to study the specific involvement of PR isoform A (PR-A) and PR-B in the anti-estrogenic effect and its mechanism of action. The results revealed that PR-B, but not PR-A, exhibited distinct anti-estrogenic effect on E2-induced cell growth, gene expression, and ER-ERE interaction in a ligand-independent manner. The anti-estrogenic effect of PR-B was also associated with heightened metabolism and increased cellular uptake of estradiol-17 beta (E2). We have also found that the B-upstream segment of PR-B alone was able to inhibit E2-induced ER-ERE interaction and cellular uptake of E2. Although PR-A alone did not affect E2-induced ER activity, it antagonized the anti-estrogenic effect of PR-B in a concentration-dependent manner. The findings suggest an important mechanism of maintaining a favorable level of ER activity by PR-A and PR-B in estrogen target cells for optimal growth and differentiation. The potential anti-estrogenic mechanism of PR-B may be exploited for breast cancer therapy.     

Risk factors for breast cancer in young women by oestrogen receptor and progesterone receptor status

We used data from 765 cases and 564 controls in the population-based Australian Breast Cancer Family Study to investigate whether, in women under the age of 40, the profile of risk factors differed between breast cancer subtypes defined by joint oestrogen and progesterone receptor status. As hypothesised, no significant differences were found.     

Influence of endocrine status on biochemical and immunocytochemical estrogen and progesterone receptor assays in breast cancer patients

Summary Breast cancer tissue from 190 patients was studied for immunocytochemically reactive estrogen and progesterone receptors (ER, PR). Parallel cytosol ER and PR assays were performed on 159 of these patients using the dextran-coated charcoal (DCC) method. For the immunocytochemical determination, monoclonal antibodies to ER (ER-ICA kit) and PR were used in an immunoperoxidase procedure. Agreement between the two techniques in postmenopausal patients was better than in the premenopausal group (ER, kappa = 0.597 vs. 0.398; PR, kappa = 0.460 vs. 0.329). The median ER cytosol concentration in receptor-positive postmenopausal patients was significantly higher than in receptor-positive premenopausal patients (87 vs. 31 fmol/mg cytosol protein, p<0.001). A similar trend was also found in the immunocytochemical ER assay (270 vs. 207 histoscore units, p>0.05). Significantly higher cytosol ER contents were found in patients with low serum estradiol concentration. The proportion of ER-negative tumors was slightly higher in the premenopausal patients by both methods. In the PR assays (biochemical or immunocytochemical) there were no significant differences between the two patient groups in the proportion of PR-negative tumors or in the median PR content in PR-positive tumors.     

Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions

ObjectiveIn endometrial cancer loss of progesterone receptor (PR, gene name PGR) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities.Methods686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray.ResultsPR protein level was significantly associated with PGR mRNA expression (P < 0.001) and patient survival (P < 0.001). Loss of PR increased with disease progression, with 23% of the primary tumours and 76% of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR.ConclusionLoss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status.     

Alcohol intake and risk of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis of epidemiological studies

The association between alcohol consumption and an increased risk of breast cancer has been established. It is still unclear however, whether this relationship differs across the estrogen receptor (ER) and progesterone receptor (PR) tumors subtypes. To provide a quantitative assessment of the association between alcohol intake and the risk of ER-/PR-defined breast cancer, we conducted a meta-analysis of cohort and case-control studies. Studies were identified by a literature search of PubMed through April 20, 2007 and by searching the reference lists of relevant articles. Summarized risk estimates (REs) with 95% confidence intervals (CIs) were calculated using random-effects models. The summarized results of the meta-analysis comparing the highest versus the lowest consumption categories showed statistically significant higher risks of developing all ER+ (27%), all ER- (14%), ER+PR+ (22%) and ER+PR- (28%), but not ER-PR- tumors. The dose-response meta-analysis showed that an increase in alcohol consumption of 10 g of ethanol per day was associated with statistically significant increased risks for all ER+ (12%), all ER- (7%), ER+PR+ (11%) and ER+PR- (15%), but not ER-PR-. A statistically significant heterogeneity of the REs across all ER+ versus ER-PR- was observed (p(heterogeneity) = 0.02). The summarized results from studies with adjustment for postmenopausal hormone use, body mass index and family history of breast cancer were higher and statistically significantly different from those without. The observed positive associations with alcohol for ER+PR+ and ER+PR- tumors cannot be explained by estrogen-dependent pathway only. Further studies need to clarify the biological mechanisms.     

晚期Luminal型乳腺癌孕激素受体表达状况与化疗疗效相关性研究

目的孕激素受体(progesterone receptor,PR)表达状况与乳腺癌内分泌治疗疗效有明确的相关性,本研究探讨PR表达状况是否也与晚期Luminal型乳腺癌化疗疗效相关。方法选取2011-03-01-2016-12-30临沂市肿瘤医院术后复发一线化疗的晚期Luminal型乳腺癌患者为研究对象,应用吉西他滨联合顺铂(GP)方案进行化疗。66例晚期Luminal型乳腺癌患者分为PR低表达组(阳性率<20%)38例和PR高表达组(阳性率≥20%)28例,均给予GP方案化疗。吉西他滨1 000mg/m^2,静脉滴入,d1、d8;顺铂25mg/m^2,静脉滴入,d1~d3。21d为1个周期,每2个周期评价疗效,共化疗2~8个周期。化疗期间出现病情进展或不能耐受的患者停止化疗。化疗结束后的患者内分泌治疗维持,直至疾病进展。结果 PR低表达组38例,完全缓解(complete response,CR)0例,部分缓解(partial response,PR)11例(28.9%),疾病稳定(stable disease,SD)25例(65.8%),疾病进展(progressive disease,PD)2例(5.3%),总有效率(CR+PR)为28.9%;PR高表达组28例,CR 2例(7.1%),PR 13例(46.4%),SD13例(46.4%),PD 0例,总有效率(CR+PR)为53.6%。2组总有效率差异有统计学意义,χ^2=5.313,P=0.021。PR低表达组和高表达组中位无进展生存期分别为9(95%CI:7.6~10.9)和12个月(95%CI:9.2~13.4),差异无统计学意义,χ^2=1.505,P=0.220。结论 PR低表达的晚期Luminal型乳腺癌患者一线GP方案化疗近期疗效差,疾病进展时间短。