乳腺癌临床诊断中雌激素和孕激素受体表达的意义

目的探讨雌激素(ER)和孕激素(PR)受体的表达在乳腺癌临床诊断中的意义。方法选取2013年3月至2014年3月间大连大学附属中山医院收治的60例乳腺癌患者,另选取大连市红星社区体检健康人员60例为对照组。所有患者术前均进行ER和PR水平测定,分析彩色多普勒超声表现特征,采用免疫组织化学染色检测ER和PR在乳腺及其周围组织中的表达。结果年龄≥40岁的乳腺癌患者的雌二醇激素含量和孕酮激素含量均高于<40岁的患者,两者比较差异有统计学意义(P<0.05)。免疫组化反应测定中,与健康成年女性比较,乳腺癌患者ER和PR水平均高(均P<0.05),且集中分布于细胞质当中。乳腺癌肿块边缘性状和血流信号的分级与ER、PR均有统计学意义(均P<0.05)。结论年龄偏大,ER和PR水平高,彩色多普勒检查显示乳腺肿块边缘不清晰、周围组织血流不丰富,提示可能患有乳腺癌。     

Prognostic value of estrogen and progesterone receptors in primary breast cancer

Estradiol receptor alone or estradiol and progesterone receptors (ER, PgR) have been measured in tumors from 307 women who were treated for primary breast adenocarcinoma. Patients received adjuvant therapy in relation to tumor stage independently of receptor status. Over a relatively short follow-up, more recurrences are recorded in patients with ER+ tumors, but at 7 years the same proportion of recurrences are registered in both groups of patients whose tumors were ER+ or ER-. Patients whose tumors were processed for both ER and PgR (148 cases) have now been evaluated after 5 years follow-up. Among 56 patients with PgR+ tumors 5 recurred, versus 22/92 in the PgR- group. 21/87 patients who had 1 to 4 invaded nodes at the time of surgery relapsed: 17/54 had PgR- tumors versus 4/33 PgR+. 6 recurrences were recorded in the 61 patients with negative nodes: 5 of them occurred in patients with PgR- tumors. In addition, recurrences observed in patients with negative receptor status occurred after a shorter disease-free interval. Analysis of the incidence of recurrences in relation to the combined ER/PgR status in patients who did not receive adjuvant therapy suggests that tumor PgR content is a more significant criterion than ER for long-term prognosis.     

Immunohistochemical image analysis of estrogen and progesterone receptors in breast cancer

Background  Recently objective quantification of immunohistochemical estrogen receptor (ER) and progesterone receptor (PgR) staining in breast cancer by image cytometry has been predominantly performed by measuring the area of positively stained cells. However, in sample preparations of immunostained hormone receptors, both the stained area and the intensity of staining vary. In this study, we performed quantification of the stained area by measuring, tailing intensity using image cytometry. Methods  Quantitative analysis of ER and PgR immunohistochemistry was performed using image cytometry. The obtained values were presented as % of positive staining (%PS). Comparison of %PS with values obtained by EIA and with clinicopathological features was performed. Results  The %PS values and the natural logarithm of the EIA levels of the hormone receptors showed a significant positive correlation for both ER and PgR. The concordance of the results obtained by the two methods was 96.3% for ER and 73.7% for PgR. The ER-%PS values of postmenopausal patients were significantly higher than those of premenopausal patients, whereas the PgR-%PS values of the former group were significantly lower than those of the latter group. Conclusions  The quantification of ER and PgR in immunostained preparations using %PS as a parameter was reproducible and showed a high correlation with values obtained by EIA. It was shown that only menopausal status affects hormone receptor levels when analyzing the relationship between %PS measurements and clinicopathological features.     

Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors

Background:We recently demonstrated that in premenopausalpatients with estrogen receptors (ER)-absent tumors, early initiation ofsystemic chemotherapy after primary surgery might improve outcome. These dataindicate a different responsiveness to chemotherapy for tumors not expressinghormone receptors. To test this hypothesis we evaluated the responsiveness topreoperative chemotherapy in patients with ER and progesterone receptors(PgR)-absent tumors. Patients and methods:Patients with biopsy-provenT₂–T₃, N_0–2 breast cancertreated at a single institution from January 1995 to August 1999 withpreoperative chemotherapy were retrospectively evaluated. ER and PgR weredetermined immunohistochemically and classified for this purpose as absent(0% of the cells positive) or positive (1% of the cells). Results:On 117 evaluable patients 72 had an objective response(61%). A significant difference in response was observed for patientswith ER and PgR absent compared with those with ER and/or PgR-positive tumors(82% vs. 57%,P = 0.03 Fishers's exact test).Pathological complete remission rates were also significantly different in thetwo groups (23% vs. 7%, respectively; P = 0.04). Conclusions:The different degree of response according to hormonereceptors expression supports the hypothesis that tumors not expressing bothER and PgR might represent a different clinical entity in terms ofchemotherapy responsiveness.     

A clinical evaluation of nuclear estrogen receptors combined with cytosolic estrogen and progesterone receptors in breast cancer

Breast cancer tissue from 95 women was simultaneously assayed for three receptors: cytosolic estrogen (CER), cytosolic progesterone (CPR), and nuclear estrogen (NER). The main objective was to determine whether the addition of NER assay to the currently accepted practice with only CER and CPR could improve the predictive capacity of receptors. Forty-two patients were studied for response to hormone therapy and 95 patients were studied for survival; the median follow-up period was 73 months (range, 8 to 300 months). The incidence of CER+, CPR+, and NER+ was 74%, 70%, and 52%, respectively. Each receptor appeared more frequently, although not significantly so, in higher age groups. Forty percent of tumors had all three receptors positive and 14% had all negative; the remaining tumors showed all possible combinations of receptors. Both the rate of response and survival curves among 70 patients with CER+ did not show any significant difference whether NER was positive or negative. Also, among 38 patients with CER+, CPR+, and NER+, there was no significant difference in the clinical outcome as compared to 17 patients with CER+, CPR+, and NER-. Among 25 patients with CER- the rare occurrence of NER+ in only three patients did not suggest any clinical implication. It is concluded, therefore, that on overall clinical grounds the current series does not support the addition of NER assay whenever data is available on both CER and CPR.     

Breast cancer estrogen and progesterone receptors

Data from 2933 consecutive cases of primary breast carcinoma, observed in our Institute from 1984 to 1994, having documented estrogen (ER) and progesterone (PR) receptor levels, were obtained from the Institute's Hospital Tumor Registry and analysed after being categorised as follows: age, less than or equal to 60 vs. >60; menopausal status, pre-menopausal vs. post-menopausal; histology, ductal vs. lobular vs. others; tumor size, T-1 vs. T-2, T-3, T-4; nodal status, N-0, vs. N+; histologic grade, 1-2 vs. 3; focality, unifocal vs. multifocal; ER status, <10 fmol/mg protein vs. greater than or equal to 15. At multivariate analysis, using a logistic model including age, histology, tumor size, nodal status, histologic grade, uni-multifocality and PGF/ER status, significant associations were, for ER status: PGR status (OR = 34.01, 95% CI:20.08-57.80), histology (OR = 3.24, 95% CI:1.85-5.67), histologic grade (OR = 2.18, 95% CI:1.38-3.42), menopausal status (OR = 2.17, 95% CI:1.26-3.74), age (OR = 34.01, 95% CI:20.08-57.80), menopausal status (OR = 5.27, 95% CI:1.43-3.33), age (OR = 1.71, 95% CI:1.13-2.59). The finding that estrogen receptor positivity was more prevalent among tumors with lobular histology seems to suggest the possibility of fundamental differences in tumor biology ductal and lobular cancers.     

p29 protein in breast cancer: relation between estrogen and progesterone receptors

An immunoradiometric assay was used to determine the presence of p29 protein in 68 breast cancer cyTOSOLS. The p29 values ranged from 0 to 1123 U/mg, with a mean value of 127 +/- 28.7 U/mg. Using a cutoff point of 20 U/mg the frequency of p29 positive tumors was about 55%. A quantitative and qualitative relation was found between p29 and estrogen receptor (ER), but not between p29 and progesterone receptor (PR). Discordance between p29 and ER status was found in 13 out of 68 tumors. Both the frequency of p29 positive tumors and the p29 values were significantly higher in postmenopausal than in premenopausal women, in a similar way to ER but different from PR. There was no difference in p29 content between primary tumor and metastasis. We did not find any relation among p29 primary tumors content and axillary lymph nodes involvement or tumor size.     

Immunohistochemical investigation of estrogen and progesterone receptors in breast tumors

Estrogen (ER) and progesterone (PR) receptor levels were assayed in 344 breast tumors. The following 4 patterns were identified: ER+ PR(+)--61%; ER+ PR- 24%; ER- PR(+)--15% and ER- PR(-)--35%. While no correlation was found between histological pattern, on the one hand, and the ER/PR ratio and age, on the other, there was one between estrogen and progesterone receptor content, on the one hand, and age, tumor size and metastatic spread to regional lymph nodes, on the other (p > 0.001).     

Enzyme immunoassay of estrogen and progesterone receptors in drill biopsy specimens from breast cancer

We have applied enzyme immunoassay (EIA) to the detection of estrogen and progesterone receptors (ER and PR, respectively) in small samples obtained by drill biopsy of primary breast cancers. Thirty patients with breast cancer underwent drill biopsy of the tumors just before mastectomy. Both the drill biopsy and surgical specimens were assayed for ER and PR in the cytosol and nuclear fractions by EIA. ER and PR in the cytosol fraction (ERc and PRc, respectively) of the drill biopsy specimens (DBS) correlated very well with those of the surgical specimens (SS): ERc (DBS) = 1.02 × ERc (SS) + 3.85 fmol/mg protein (r = 0.958) and PRc (DBS) = 1.05 × PRc (SS) + 3.87 fmol/mg protein (r = 0.958). ER and PR in the nuclear fraction (ERn and PRn, respectively) of the drill biopsy specimens also correlated very well with those of the surgical specimens: ERn (DBS) = 1.02 × ERn (SS) + 59.18 fmol/mg DNA (r = 0.932) and PRn (DBS) = 0.98 × PRn (SS) + 54.28 fmol/mg DNA (r = 0.898). These results demonstrate that EIA for ER and PR of the drill biopsy specimens is a very useful method for the estimation of the receptor status of breast cancers.     

Prognostic significance of progesterone receptors alone or in association with estrogen receptors in human breast cancer

Estrogen (ER) and progesterone (PgR) receptors were measured simultaneously in 1144 consecutive breast cancer patients to determine the distribution of patients according to receptor and menopausal status when receptor occurrence rates were considered. The prognostic significance of PgR, either alone or in association with ER, was studied on 187 consecutive breast cancer patients treated only by radical mastectomy. All the cases, as regards axillary node status, were pathologically assessed as node negative. These patients did not receive any adjuvant treatment after mastectomy. At 36 months after mastectomy, the follow-up indicated that PgR- patients have a worse prognosis than PgR+ ones. This is evident when PgR alone is considered as a prognostic factor as well as when it is used to identify, within ER+ cases, those with a higher probability of relapse. In conclusion, it can be stated that although PgR status is an independent prognostic factor, it is useful to evaluate ER and PgR simultaneously for better patient management.     

血清睾酮水平与乳腺癌雌、孕激素受体表达的相关性研究

目的:回顾性研究血清睾酮（testosterone,T）水平与乳腺癌雌激素受体（estrogen receptor,ER）,孕激素受体（progesterone receptor,PR）表达的相关性。方法:回顾性分析2016年1月至2018年12月在南京市妇幼保健院进行体检和治疗的63例健康女性,99例良性肿瘤,204例乳腺癌的临床病理资料,比较三组之间的血清睾酮水平的差异。将所有204例乳腺癌患者根据睾酮水平由低到高排序,按四分位数分为4组,采用Logistic回归比较不同睾酮水平下4组乳腺癌患者ER、PR、Her2表达状态的比值比（OR）。结果:乳腺癌组血清睾酮水平与乳腺良性肿瘤组、健康对照组相比差异均无统计学意义（P＞0.05）。ER+和PR+乳腺癌患者中血清睾酮水平分别高于ER-和PR-患者,而Her2+乳腺癌患者中血清睾酮水平低于Her2-患者,差异均有统计学意义（P＜0.05）。采用Logistic回归计算OR值,根据绝经与否进一步分层,其中T≥0.44 ng/mL组相对于T≤0.22 ng/mL组ER阳性表达的总体OR值为2.46（95%CI=1.04~5.86,P=0.042）,绝经前OR值为3.77（95%CI=1.11~12.80,P=0.034）,绝经后OR值为1.05（95%CI=0.28~3.92,P=0.945）;T≥0.44 ng/mL组相对于T≤0.22 ng/mL组PR阳性表达的总体OR值为3.69（95%CI=1.60~8.49,P=0.002）,绝经前OR值为4.80（95%CI=1.51~15.23,P=0.008）,绝经后OR值为1.78（95%CI=0.47~6.71,P=0.396）,结果显示绝经前乳腺癌患者中ER、PR的阳性表达与血清睾酮水平呈现出明显的正相关性;而Her2阳性表达与血清睾酮水平在总体、绝经前、绝经后乳腺癌患者中均未表现出明显的负相关性。结论:高血清睾酮水平与乳腺癌ER、PR的阳性表达呈正相关,在绝经前乳腺癌患者中表现尤为显著。血清睾酮水平可以作为预测绝经前激素受体状态的标志物之一。     

Immunological quantitation of nuclear receptors in human breast cancer: relation to cytosolic estrogen and progesterone receptors

Nuclear estrogen receptors (ERn) can now be reliably analyzed using the monoclonal estrogen receptor enzyme immunoassay. In a consecutive series of 135 breast cancer biopsies, ERn as well as cytosolic estrogen receptor (ERc) and progesterone receptor (PgR) concentrations were determined to evaluate whether ERn assays provide additional valuable information for the clinical management of the disease. Furthermore, by performing analyses on this relatively large number of patients, we sought explanations for the occurrence of the receptor profiles of ERc negative PgR positive and ERc positive PgR negative, which are found in a significant proportion of tumor biopsies. Eight-four % of all tumors are classified as ERn positive (greater than or equal to 10 fmol/mg nuclear extract protein) using the monoclonal assay technique. Two trends are evident: ERc positivity was found to be associated with ERn positivity (greater than or equal to 10 fmol/mg cytosol protein) in 98% of the cases investigated; and PgR positivity (greater than or equal to 10 fmol/mg cytosol protein) was found to be associated with ERn positivity in 95% of the cases investigated. However, a major proportion (approximately 28%) of ERn positive tumors are either ERc negative or PgR negative. The pattern of ERc negative ERn positive occurs almost exclusively among younger women, most of whom also had detectable amounts of PgR in their tumor tissues, while the pattern of ERn positive PgR negative occurs primarily among older women. ERn concentration was found to be significantly correlated to the concentration of both PgR and ERc. While the correlation between ERn and PgR was found to be strongest among women younger than 50 years of age, the correlation between ERn and ERc was strongest among women older than 50 years. Young women were found to have a significantly higher proportion of total tissue estrogen receptor present as ERn than older women (27 versus 14%). The information obtained by performing ERn analyses concurrently with or in place of ERc and PgR analyses does not appear to be valuable for the clinical management of the disease. However, this new method for determination of ERn is a significant advance in receptor technology that permits reevaluation of established enigmas concerning the biology and natural history of breast cancer.     

Variation of estrogen and progesterone receptor status in breast cancer after tamoxifen therapy

In the present paper we have studied the quantitative variations in estrogen (ER) and progesterone receptor (PR) content of breast cancer induced by tamoxifen. In addition to receptors, hormonal levels of estradiol, progesterone, prolactin, FSH, LH and testosterone were also measured. The cases included in our study were consecutively selected among those breast cancers in which an aliquot of the tissue sample sent for analysis of the steroid receptors was positive for cancer and also found to have at least one of the steroid receptors positive, not only in the biopsy but also in the surgical specimen. Following this criterion, we finally collected 14 cases of breast cancer treated daily with 30 mg of tamoxifen during an interval of 3 weeks from the initial biopsy to the final surgery. From our results we can conclude that tamoxifen reduced significantly the ER concentration while no changes were observed in PR values. Concerning hormones, while in premenopausal patients tamoxifen induced a rise in plasma estradiol, in postmenopausal women the only modification observed was a decrease in plasma FSH. The variation in steroid receptor content under tamoxifen therapy may also contribute to the evaluation of the hormone dependency of gynecologic malignancies.     

Changing behavior of estrogen and progesterone receptors with metastasis or recurrence of breast cancer

Changes in level of estrogen receptor (ER) and progesterone receptor (PgR) and their affecting factors were studied with metastasis or recurrence of breast cancer. Since 1983, from 177 patients, 443 specimens were obtained and 244 simultaneous and 122 sequential pairs were compared. The consistency rate was 81% for both ER and PgR with simultaneous comparison,and 69% for ER and 71% for PgR with sequential comparison, mainly due to positive-to-negative change, and less than 10% of negative-to-positive change. Positive-to-negative change was prominent with intervening endocrine treatment, and it was significant (p=0.015) for ER by multiple regression analysis of age, interval of sampling and from prior surgery, intervening chemotherapy, endocrine therapy and human epidermal growth factor receptor 2 (HER 2). Based on recent data of ER and PgR, feasible treatment seems to be planned, because about 30% of them are different from that of primary lesion.     

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.     

Characterization of estrogen and progesterone receptors and the dissociated regulation of growth and progesterone receptor stimulation by estrogen in MDA-MB-134 human breast cancer cells

We have examined the properties of the estrogen receptor and progesterone receptor in MDA-MB-134 human breast cells and have evaluated the effects of estrogen on cell proliferation and progesterone receptor levels in these cells as indices of hormonal sensitivity. These cells contain high levels of estrogen receptor (approximately 1.5 pmol/mg DNA) and low levels of progesterone receptor (0.15 pmol/mg DNA). More than 80% of the estrogen receptor is found in the nuclear fraction in the absence of estrogen, and the Kd of the receptor for estradiol is approximately 1.5 X 10(-10) M. Upon exposure to estradiol, the receptors become occupied, but there is no processing or apparent decrease in either nuclear or total cellular estrogen receptor content, as can be seen in MCF-7 human breast cancer cells. The nuclear estrogen receptor sediments as a 4.6 S species on high salt sucrose gradients, and it can be detected on sodium dodecyl sulfate-polyacrylamide gel immunoblot analysis as a species of molecular weight 65,000, identical to that of the MCF-7 estrogen receptor, using the monoclonal antibodies D75P3 gamma and H222Sp gamma prepared against the MCF-7 estrogen receptor. The estrogen receptor shows binding selectivity for estrogens and antiestrogens, and its affinity for ligands follows the order diethylstilbestrol (190%) greater than estradiol (100%) greater than estriol (13%) greater than tamoxifen (3%), as expected for estrogen receptor. Hence the receptor appears normal in many of its physicochemical properties and in terms of its binding affinity and specificity for estrogens and antiestrogens. Control cells contain low levels of progesterone receptor that display high affinity (Kd = 6 X 10(-9) M) for the synthetic progestin R5020, but exposure to estradiol (10(-11)-10(-7)M) fails to increase cellular progesterone receptor levels. In contrast, estradiol markedly stimulates the rate of cell proliferation, while tamoxifen suppresses the growth of control and of estradiol treated cells. Hence, our data show that these cells, which contain substantial levels of estrogen receptor, respond to estrogen with enhanced cell proliferation but fail to have their progesterone receptor level modulated by estradiol. These cells represent an interesting and unusual situation in which estrogenic regulation of proliferation and the stimulation of progesterone receptor are dissociated. These cells should prove useful in further evaluation of estrogenic regulation of cell proliferation and specific protein synthesis in human breast cancer.     

Role of progesterone receptors in breast cancer

It has been demonstrated that progesterone receptors (PRs) are at least as valuable as estrogen receptors (ERs) for predicting outcome in breast cancer patients. Retrospective analysis indicates that the presence of PRs may be the second most critical factor, after the number of positive nodes, in predicting disease-free survival, with a correlation between length of survival and number of tumor PRs. The presence of PRs has been shown to be of value for predicting response in both early and advanced breast cancer patients. In studies of assay consistency, major discordance rates were minimal in simultaneous assays, but extremely high in sequential assays of tumors that were PR-positive in initial assay. The responsible factor was interim endocrine therapy, and it was subsequently determined that the prognosis was worse for those patients whose tumors lost PR between assays.