甾体类激素受体在乳腺癌发生与发展中的变化

甾体类激素如雌激素和孕激素是调节正常乳腺组织发育的重要内分泌因素，同时也在诱导乳腺癌变中发挥重要作用。甾体类激素通过相应受体的介导对其靶细胞进行作用，这些甾体类激素受体在乳腺癌的发生和进展过程中发生了一系列有意义的变化；另外近年还发现了新的雌激素受体(ER)亚型ER-β。这些发现为研究乳腺癌发生和内分泌治疗耐药机制提供了新的线索。     

趋化因子及其受体在乳腺癌中的研究进展

乳腺癌已成为妇女最常见的恶性肿瘤,其发病率占妇女恶性肿瘤第一位,且有逐年上升趋势。乳腺癌的远处转移缩短了无病生存期,增加了病死率,也是目前临床上的治疗难点。而肿瘤的侵袭与转移是一个主动过程,与白细胞迁移有许多相似之处,由趋化因子及其受体严密调控。     

胎儿乳腺的雌激素受体与乳腺癌

The estrogen receptor in bilateral breasts of 36 6 to 10-month fetuses (17 male, 19 female) were examined. All fetal breasts had ER positive cells (greater than 50-90%). The ER levels were similar regardless of sex and age. When the ER status of 84 female breast cancer patients was analysed, ER was considered as an essential but not the only etiologic factor in mammary carcinogenesis. A positive correlation between the degree of differentiation and the ER level of breast cancer cells was demonstrated and the ER level did not correlate with the clinical staging of breast cancer. The results are briefly discussed in relation to the rationale of hormonal therapy of breast cancer.     

瘦素受体基因变异与乳腺癌发生的关系

目的 探讨瘦素受体基因(OB-R)第exon 4、6、9、20核苷酸位点变异与乳腺癌发生的关系.方法 采用体外基因扩增、测序的方法,检测155例乳腺癌患者肿瘤组织、56例乳腺良性病组织和100例健康人的抗凝血中OB-R基因核苷酸位点变异情况.结果 OB-R基因第exon 4在乳腺癌组、乳腺良性病组和健康对照组受检者中均未发生核苷酸位点变异,而第exon 9的1029核苷酸位点均发生了碱基置换,3组之间比较,差异无统计学意义(P=0.574).第exon 6的668核苷酸位点发生了碱基颠换,导致多态性Gln223Arg.Gln223Arg的GG、GA、AA基因型在乳腺癌组中的表达频率分别为70.9%、17.4%和12.3%,在乳腺良性病组中的表达频率分别为80.4%、14.3%和5.4%,在健康对照组中的表达频率分别为81.0%、16.0%和3.0%;G和A等位基因在乳腺癌组中的表达频率分别为79.1%和20.8%,在乳腺良性病组中的表达频率分别为87.5%和12.5%,在健康对照组中的表达频率分别为89.0%和11.0%.3组Gln223Arg基因型和等位基因表达频率比较,差异有统计学意义(x2=16.11,P＜0.005;x2=11.41,P＜0.01).第exor 20的3057核苷酸位点发生了碱基颠换,导致多态性Pro1019Pro.Pro1019Pro的GG、GA、AA基因型在乳腺癌组中的表达频率分别为11.6%、30.3%和56.1%,在乳腺良性病组中的表达频率分别为32.1%、44.0%和28.5%,在健康对照组中的表达频率分别为32.0%、45.0%和23.0%;G和A等位基因在乳腺癌组中的表达频率分别为26.8%和73.2%,在乳腺良性病组中的表达频率分别为51.8%和48.2%,在健康对照组中的表达频率分别为54.5%和45.5%.3组Pro1019Pro基因型和等位基因变异频率比较,差异有统计学意义(x2=6.56,P＜0.03;x2=5.45,P＜0.05).乳腺癌组超重和肥胖者第exon 6、exon 20发生碱基颠换的频率明显高于正常体重者,差异有统计学意义(P＜0.05,P＜0.01).结论 OB-R基因第exon9核苷酸位点变异与乳腺癌发生无关,而第exon 6和第exon 20核苷酸位点变异可能与乳腺癌的发生风险有关.

Abstract：

Objective The aim of this study was to investigate the relationship of the mutations of leptin receptor gene exon 4, exon 6, exon9, and exon20 with the tumorigenesis of breast cancer. Methods Genomic DNA was extracted from breast cancer tissues of 155 patients, benign lesions of 56 patients and normal tissues and blood samples from 100 health control subjects. The leptin receptor genes were assayed with polymerase chain reaction (PCR) amplification and direct sequence analysis. Results Nucleotide substitutions no mutations were found at exon 4, and nucleotide substitutions occurred at codon 1029 in exon 9, no significant difference among the three groups (P =0.574). The nucleotide substitutions at codon 668 in exon 6 resulted in Gln223Arg polymorphisms. The occurring frequencies of GG, GA, AA in breast cancer, breast benign lesions tissues and health tissues control group were 70.9% and 17.4%, 12.3%;80.4%, 14.3% and 5.4%; and 81.0%, 16.0%, and 3.0%, respectively. Alleles of G and A in the three groups were 79.1% and 20.8%, 87.5% and12.5%, and 89.0% and 11.0%, respectively. Compared the Gln223Arg genotype with the three allele groups, there were significant differences (x2 = 16. 11 ,P ＜0.005 and x2 = 11.41, P ＜ 0. 01 ), respectively. The nucleotide substitutions at codon 3057 in exon 20 resulted in Pro1019Pro polymorphisms. The occurrence frequencies of GG, GA, AA in the breast cancer,benign disease and health control groups were 11.6%, 30.3% and 56. 1%; 32.1%, 44.0% and 28.5%;and 32.0%, 45.0% And 23.0%, respectively. Alleles of G and A in the three groups were 26.8% and 73.2% ,51.8% and 48.2%, and 54.5% and 45.5%, respectively. There are significant differences among the three groups (x2 = 6.56, P ＜ 0. 03 and x2 = 5.45, P ＜ 0. 05 ), respectively. Nucleotide substitutions occurred at relatively high frequencies at exon 6 and exon 20 in obese and overweight breast cancer patients compared with those in normal weight breast cancer patients, there were significant differences ( P ＜ 0.05and P＜0.01). Conclusions Our findings show that there is no relationship between the variations of leptin receptor gene exon 9 and tumorigenesis of breast cancer. The variation rate of leptin receptor gene exon 6 and exon 20 are significantly increased in the obese and overweight breast cancer paztients.     

雌激素受体β与乳腺癌

乳腺癌是一种激素依赖性肿瘤。雌激素受体α（ERα）在雌激素介导的乳腺癌发生、发展中起重要作用。然而,最近研究发现乳腺癌细胞的雌激素受体存在另一亚型——雌激素受体β（ERβ）,也可能在乳腺癌的发生、发展中起重要作用。与ERd的作用不同,ERβ在细胞实验和动物模型研究中表现出对乳腺癌细胞增殖抑制作用。文章从ERβ与ERd及孕激素受体（PR）的关系、乳腺癌浸润与转移及对内分泌治疗的影响等方面阐述其与乳腺癌的关系。     

趋化因子受体CXCR4在乳腺癌中的表达及临床意义

目的：探讨乳腺癌中趋化因子受体CXCR4的表达及临床意义。方法：采用免疫组化S—P染色法检：测乳腺癌、乳腺增生组织、及乳腺纤维腺瘤中CXCR4表达,分析CXCR4在乳腺癌中表达与患者淋巴结转移状态、Her2、PCNA关系。结果：CXCR4在乳腺癌组织中高表达,与乳腺增生组织及乳腺纤维腺瘤组织中表达有显著性差异,与患者淋巴结转移状态、Her2、PCNA密切相关。结论：CXCR4在乳腺癌中高表达,可以作为乳腺癌患者预后的一个指标,为寻找新的乳腺癌治疗靶点提供了依据。     

趋化因子受体CXCR4在乳腺癌中的表达及临床意义

目的:探讨乳腺癌中趋化因子受体CXCR4的表达及临床意义.方法: 采用免疫组化S-P染色法检测乳腺癌、乳腺增生组织、及乳腺纤维腺瘤中CXCR4表达,分析CXCR4在乳腺癌中表达与患者淋巴结转移状态、Her2、PCNA关系.结果: CXCR4在乳腺癌组织中高表达,与乳腺增生组织及乳腺纤维腺瘤组织中表达有显著性差异,与患者淋巴结转移状态、Her2、PCNA密切相关.结论: CXCR4在乳腺癌中高表达,可以作为乳腺癌患者预后的一个指标,为寻找新的乳腺癌治疗靶点提供了依据.     

耐药基因及雌孕激素受体在乳腺癌中的表达及意义

本文用免疫组化法对１５例乳腺癌做了多药耐药基因产物Ｐ１７０及谷胱甘肽Ｓ－转移酶（ＧＳＴπ）以及雌孕激素受体（ＥＲ，ＰＲ）的检测。浸润性导管癌１４例，粘液腺癌１例。检测结果雌孕激素受体共同表达率为６６．７％（１０／１５），Ｐ１７０过度表达为６６．７（１０／１５），ＧＳＴπ过度表达为５５．３％（８／１５）。ＥＲ、ＰＲ表达与肿瘤的分化程度有关，即分化好的乳腺癌标记率较高，提示预后较好。结果表明多数乳腺癌     

Multiple steroid receptors in human breast cancer

Summary Histopathologic features (tumor cell density, histological type, and histoprognostic grade) were analyzed in 314 breast cancers investigated for estrogen (E) and progestin (P) receptors (R). The presence of PR is associated with the presence of ER. A relationship was found between the acinoductal differentiation of the lesions and the presence of SR: the more differentiated the carcinoma, the higher the frequency of ER. HPG III carcinomas have the lowest frequency of positive ER and HPG I tumors the opposite: the likelihood of the presence of SRs is inversely correlated with HPG. No statistically significant relationship existed between tumor cell density (TCD) and the presence of ER or ER content. Similar findings were observed for the stromal reaction. The results are discussed with respect to the biological significance of SR and histopathologic features: SR presence could be correlated with (1) a differentiated state of the tumors and (2) a slow rate of cellular replication.     

International comparisons concerning breast cancer and steroid receptors

In 1060 Japanese patients, 58 and 36% of breast tumors contained estrogen (ER) and progesterone receptors (PR), respectively. These rates are somewhat lower than those in Western countries. The slightly lower incidence of receptors in Japanese patients is due to significantly lower incidence of receptor positive tumors in postmenopausal Japanese patients than in postmenopausal Western patients. However, in postmenopausal overweight (greater than or equal to 60 kg) Japanese patients the rate of ER + breast cancer was comparable to that in postmenopausal Western patients. The effect of overweight on an increased incidence of Japanese breast cancer was found to be confined to postmenopausal women. In 260 Japanese breast cancer patients, the regression rates to endocrine therapy were 10% for ER-tumors, 48% for ER + tumors, and 66% for ER +, PR + tumors, which are similar to those reported in Western countries.     

Time-dependent relevance of steroid receptors in breast cancer.

PURPOSE: To analyze the time-dependent prognostic role of the investigated variables, considered, when appropriate, on a continuous scale, for the purpose of evaluating and describing the interrelationships between clinically relevant patient and tumor characteristics (age, size and histology, and estrogen receptor [ER] and progesterone receptor content) and the risk of new disease manifestation. PATIENTS AND METHODS: We applied a flexible statistical model to a case series of 1,793 patients with axillary lymph node-negative breast cancer with a minimal potential follow-up of 10 years. To avoid a potential confounding effect of adjuvant treatment, only patients given local-regional therapy until relapse were considered. RESULTS: ER content and tumor size (adjusted for all the other covariates) showed a time-dependent relationship with the risk of new disease manifestations. In particular, ER content failed to show a prognostic effect within the first years of follow-up; thereafter, a positive association with risk of relapse was observed. For tumor size, within the first years of follow-up, the risk of relapse was directly related to size for only tumors up to 2.5 cm in diameter; thereafter, the impact on prognosis progressively decreased. CONCLUSION: The availability of a long follow-up on a large breast cancer series, as well as the use of innovative statistical approaches, allowed us to explore the functional relation between steroid receptors and clinical outcome and to generate a hypothesis on the involvement of ER in favoring long-term metastasis development.     

Relationship between PRL levels and steroid receptors in breast cancer

The role of PRL in human breast cancer is still debated. We examined 259 women undergoing surgery for breast cancer (K = 183) and for other diseases (n = 76). In all subjects blood samples were taken for the RIA assay of PRL, during the preanaesthesia. In the breast cancer specimens, estrogen (ER) and progesterone (PGR) receptors were assayed and T.N.M. was evaluated. PRL mean values were assayed and T.N.M. was evaluated. PRL mean values were found to be above the normal range in both groups. PRL values in ER+ and PGR+ were lower than in ER- and PGR-. We also divided the patients into two groups (PRL values greater than 50 or less than 50 ng/ml). The difference between the two groups was significant for ER (p less than 0.005) and PGR (p less than 0.05), using Student's unpaired t-test. Besides this, we observed a significant negative linear correlation between PRL values and receptor values. The finding of this correlation suggests that high PRL values could be associated with unfavourable prognosis in breast cancer.     

Growth factor receptors and the progression of breast cancer

Interference with autocrine or paracrine loops offers a potential means of treatment of tumors which currently lack effective therapies. Hormonally responsive breast cancers generally respond to treatment with antiestrogens but a frequent occurrence is an outgrowth of populations of tumor cells that are no longer dependent on estrogen for growth. If the acquisition of the ability to constitutively express growth factors or growth factor receptors is associated with this form of tumor progression, identification of the growth factors and their receptors having the capability of reducing the dependence on estrogen for growth is an important first step in the design of strategies aimed at interfering with their function. Experimental systems employing transfection with eukaryotic expression vectors are described that are designed to test the hypothesis that overexpression of epidermal growth factor receptor or the related protein C-ERB-B2 may confer an increased growth rate under conditions of estrogen deprivation. The transfected cells are also being used to explore the molecular mechanisms underlying the regulation of epidermal growth factor receptor expression by estrogen.     

Simultaneous micro measurement of steroid receptors in breast cancer.

The oestradiol (RE) and progesterone (RP) receptor levels were analyzed in 26 tumour fragments (200-500 mg) from breast cancer patients. After pulverization of tissue, one part was analyzed by the routine dextran-coated charcoal (DCC) method and the other by a micromethod as follows: (i) cytosol incubation using the DCC method but in the simultaneous presence of [3H]oestradiol and [3H]R5020 (ii) extraction of the steroids bound to the receptor by precipitation with ethanol/TCA (iii) high pressure liquid chromatography (HPLC) on a modular system, with a C185 microns column and an elution by gradient mixture methanol/water. The fractions were collected and the radioactivity counted. The separation of oestradiol from R 5020 was rapid and complete. In addition dexamethasone was separated by this system making possible triple measures of RE, RP and glucocorticoid receptors. A highly significant correlation was obtained between the 2 methods: RE = 0.996, P less than 0.001; RP r = 0.975, P less than 0.001, implying that the thresholds of positivity, i.e. for therapeutic decisions, remain unchanged. Simultaneous measurement of RE and RP in a single needle biopsy is possible with this micromethod.     

Electrocautery: Effects on steroid receptors in human breast cancer

The determination of steroid receptors in human breast cancers has assumed increasing importance over the past several decades. Improper handling of the specimens could affect results obtained. This study details the effects excessive levels of heat that occur with the use of electrocautery can have on steroid receptor quantities and localization. Twelve resected primary and metastatic human breast cancers were analyzed for cytoplasmic and nuclear receptors by biochemical analysis. In addition, steroid binding was determined by direct fluorescent histochemical techniques. To a portion of each resected specimen a Bovie^c was applied to simulate electrocautery resection. Analysis of the different portions of the same tumor revealed that there was a decrease in measurable cytoplasmic receptor in all cauterized specimens and a concomitant increase in the nuclear receptor. A similar shift in steroid binding was noted in all the specimens analyzed by fluorescent histochemical techniques. The results of this study show that the application of excessive heat to human breast cancers will lead to false negative biochemical steroid receptor determination by shifting the receptors intranuclear.     

Association of plasminogen activator activity and steroid receptors in human breast cancer

Plasminogen activating activity (PAA) has been determined in 105 human breast cancer cytosols with a colorimetric assay. PAA has been related to steroid receptors in the same cytosols. A strong positive correlation between PAA and progesterone receptor levels was found (Spearmans coefficient of rank correlation, R = 0.74, P < 0.001). PAA discriminates between progestrone receptor-positive and -negative tumours, irrespective of oestradiol receptor content. It is suggested that PAA is a marker of functional oestradiol receptor and that fibrinolytic activity may be a causative factor in the low metastatic potential of progesterone receptor-positive tumours.