新型雌激素对女性血透患者骨质疏松的临床干预

目的：观察雌激素他莫昔芬对维持性血液透析（ MHD）女性患者骨质疏松的治疗作用。方法选取50例MHD女性患者按有／无骨质疏松分为A组（n＝26）与B组（n＝24）,再将A组随机分为A1组（n＝13,服用他莫昔芬、骨化三醇和碳酸钙）与A2组（ n＝13,不服用他莫昔芬,余同A1）;观察治疗前后（12个月）患者疗效、副作用及血清雌二醇（ E2）、骨形态发生蛋白－2（BMP－2）、全段甲状旁腺素（iPTH）等指标的变化;并以E2、BMP－2水平对入组患者骨质疏松的诊断进行ROC曲线分析。结果A1组疗效显著优于A2组（P＜0．05）,两组副作用差异无统计学意义（P＞0．05）;治疗前A组E2、BMP－2水平显著低于B组,治疗后A1组E2、BMP－2水平显著高于A2组（P＜0．05）,治疗前后iPTH、Ca水平差异无统计学意义（P＞0．05）;多元线性回归提示治疗前A组及治疗后A2组iPTH与BMD值呈负相关（P＜0．05）,E2、BMP－2、Ca与骨密度（BMD）值呈正相关,且E2、BMP－2对BMD值影响最大。 B组及治疗后A1组各指标与BMD值无线性回归关系。 ROC曲线提示E2、BMP－2与入组患者BMD值关系密切。结论他莫昔芬可能是通过提高MHD女性患者体内E2、BMP－2水平从而安全有效的治疗骨质疏松,且E2、BMP－2是影响MHD女性患者骨质疏松的重要因子。     

Proportion of estrogen or progesterone receptor expressing cells in breast cancers and response to endocrine therapy

Immunohistochemical determination of ER/PR status has been the gold standard in clinical practice of breast cancer for decades. A cut-off of ‘1%’ is commonly used; however, this is not supported by strict evidence. How the proportion of ER/PR-positive cells influences the response to endocrine therapy has been scarcely reported, either. To address these issues, 486 and 663 invasive breast cancer cases treated with or without adjuvant tamoxifen respectively (median follow-up period, 12.8 years) were enrolled, and effect of tamoxifen treatment was compared among ER/PR-positive or -negative groups immunohistochemically determined using various cut-offs. Tamoxifen significantly improved 5 years disease-free survival in ER/PR-positive, but not in ER/PR-negative, cases even using immunohistochemical >0% cut-off. Cases with ≥67% ER/PR expressing cells responded to tamoxifen by far the best. Patients having tumors without any ER/PR-positive cells should be excluded from endocrine therapy, whereas this therapy should be strongly recommended for those with ≥67% ER/PR-positive cells.     

口服和经皮肤途径雌激素替代治疗对手术绝经妇女围绝经症状和T淋巴细胞雌激素受体亚型表达的影响

目的研究口服和经皮肤途径的雌激素替代治疗（ERT）对手术绝经妇女围绝经症状和T淋巴细胞雌激素受体（ER）亚型表达的影响。方法手术绝经妇女随机分为使用雌二醇口服片1mg／d（口服组）和雌二醇贴片1．5mg／w（皮贴组）,用药3个月。评估用药前后围绝经症状、血雌二醇（E2）和卵泡刺激素（FSH）水平,实时荧光定量逆转录-聚合酶链反应（RT-PCR）技术检测T淋巴细胞ERα、ERβmRNA表达,免疫荧光法和免疫印迹法检测ERα、ERβ蛋白质表达。结果口服组和皮贴组用药后围绝经症状均明显改善,血清E2水平明显升高,FSH水平明显降低,两组间无明显差异。两组用药后T淋巴细胞ERαmRNA和蛋白质表达均明显高于用药前,ERβmRNA和蛋白质表达有增加趋势,两组间无明显差异。结论口服和经皮肤途径的ERT均能改善手术绝经妇女的围绝经症状,推测雌激素是通过与人T淋巴细胞ERα结合后影响绝经后的T淋巴细胞功能。     

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.     

Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells

Background

A significant percentage of estrogen receptor (ER)–positive breast cancers are resistant to tamoxifen therapy. Seven in Absentia Homolog 2 (SIAH2), an E3 ubiquitin protein ligase, has been shown to be associated with resistance to antiestrogens. We sought to assess its role in the resistance of a breast cancer cell line, MCF-7, to the ER antagonist, tamoxifen.

Materials and methods

A bioinformatic approach was used for the analysis of SIAH2 expression in breast cancer. MCF-7 and MDA-MB-231, which are ER-positive and -negative breast cancer cell lines, respectively, were used for in vitro studies. SIAH2 and ER-α were selectively knocked down in these cell lines with small-interfering RNAs. Knockdowns were confirmed with Western blot analysis and quantitative real-time polymerase chain reaction. Cells with SIAH2 knockdown were treated with tamoxifen and compared with controls.

Results

Knockdown of SIAH2 followed by treatment with tamoxifen resulted in a significant decrease in the sensitivity of treated ER-positive cells. Of note, knockdown of SIAH2 resulted in downregulation of ER-α, whereas knockdown of ER-α had minimal effect on SIAH2. Consistent with this result, the bioinformatic analysis of clinical data revealed that SIAH2 expression is significantly correlated with ER positivity in human breast cancers, and low SIAH2 expression is associated with a poorer response to tamoxifen.

Conclusions

SIAH2 appears to be an important modulator of tamoxifen sensitivity in ER-positive MCF-7 cells, mediated, at least in part, through regulation of ER-α expression. Low expression of SIAH2 may be one of the mechanisms that contribute to tamoxifen resistance in human breast cancer.     

Tailoring adjuvant treatments for the individual breast cancer patient

BACKGROUND: Chemotherapy, tamoxifen and ovarian function suppression have all demonstrated their effectiveness for treating women with early breast cancer. Treatment selection for individual patients, however, requires estimates on the magnitude of treatment effects to be achieved from the application of each modality. Unfortunately, information currently available is insufficient to properly tailor adjuvant treatments. METHODS: We consider predictive factors to improve our understanding about selection of adjuvant therapies, reassessment of data from previous clinical trials and design of future studies. RESULTS: Estrogen receptor (ER) and progesterone receptor (PgR) are the primary measures available today to tailor adjuvant therapies. Patient age/menopausal status (ability to obtain treatment effects via ovarian function suppression), measures of the metastatic potential of the tumor (such as number of positive axillary lymph nodes), and concurrent use of chemotherapy and tamoxifen are other factors that modify the magnitude of relative effect associated with chemotherapy and endocrine therapies. The Subpopulation Treatment Effect Pattern Plots (STEPP) method displays the patterns of treatment effects within randomized clinical trials or datasets from meta-analyses to identify features that predict responsiveness to the treatments under study without relying on retrospective subset analysis. Confirmation of hypotheses using independent clinical trial databases is recommended. DISCUSSION: All findings from clinical trials and meta-analyses should be presented primarily according to steroid hormone receptor status and patient age. Future studies should be designed as tailored treatment investigations, with endocrine therapies evaluated within populations of patients with endocrine responsive tumors, and chemotherapy questions focused within populations of patients with endocrine nonresponsive disease.     

肥大乳房和小乳房乳腺组织中雌激素受体的表达

目的探讨肥大乳房和小乳房与乳腺组织内雌激素受体含量的关系。方法用葡聚糖包裹活性炭液单点测定法测定肥大乳房和小乳房各13例乳腺组织内雌激素受体的含量。结果肥大乳房组雌激素受体含量为(533±570)fmolmg(注f为万亿分之一),小乳房或乳房萎缩组为(116±086)fmolmg,两组间比较差异有显著性意义(P<005)。结论肥大乳房及巨乳症的发生,可能与雌激素受体含量升高有关;而乳腺组织中雌激素受体含量减少或敏感性较低,可能是乳房发育不全的成因。     

Type and Duration of Exogenous Hormone Use Affects Breast Cancer Histology

Background It is unclear whether hormone replacement therapy (HRT), in addition to increasing risk for breast cancer, affects the type of breast cancer diagnosed. We conducted this investigation to assess whether the type of hormone used (none, estrogen, progesterone, or combined) and duration of use influences subsequent breast cancer histology. Methods We performed a retrospective cohort analysis among women listed as incident cases of breast malignancy in the Kaiser Permanente Northern California Cancer Registry during 2003 (n = 2830). Type and duration of hormone used (none, estrogen, progesterone, or combined) before breast cancer diagnosis was obtained from electronic pharmacy records. The association between type and duration of hormone use with characteristics of subsequent breast cancers was examined. Results Among women aged >50 years (n = 1701), any use of estrogen, progesterone, or combination therapy was not associated with an increased risk of estrogen receptor (ER)-positive disease. However, >6 months’ use of combined HRT increased the odds of ER-positive tumors (odds ratio, 1.65; 95% confidence interval, 1.07–2.5; P = .02). Estrogen HRT patients were more likely than nonusers to present with low-grade (P = .05), and early-stage tumors (P = .03). This trend was not seen in combined HRT users. Conclusions Short-duration HRT did not increase the likelihood of ER-positive breast cancer. However, prolonged duration of combined HRT, but not estrogen or progesterone alone, resulted in a marked increase in ER-positive disease. Our findings suggest that the effect of combined HRT on breast cancer incidence or progression is not immediate and that long-term use is more likely to affect breast cancer histology.     

雌激素受体β水平预测乳腺癌预后的研究进展

乳腺癌是一种激素依赖性肿瘤,雌激素在其发生、发展中起重要作用,而雌激素须通过雌激素受体（ER）介导发挥生物学作用。ER是由其基因编码的一种核转录因子,包括α和β两个亚型。相关研究表明ERα表达缺失或突变与乳腺癌预后不良有关,而ERβ表达与乳腺癌预后的相关性,体外实验与临床研究的结果不尽相同。本文就ERβ及其亚型在乳腺癌发生、发展和内分泌治疗中的作用以及对乳腺癌预后的预测价值做一综述。     

雌激素受体真核表达质粒对乳腺癌耐药细胞耐药性和细胞增殖的影响

目的　研究雌激素受体 (ER )表达质粒对MCF 7/ADR乳腺癌阿霉素耐药细胞耐药性和细胞增殖的影响。方法　Westernblot法检测MCF 7细胞和MCF 7/ADR细胞ER状态。构建ER的真核细胞表达质粒 pCER ,导入MCF 7/ADR细胞 ,流式细胞仪检测细胞周期分布 ,MTT法检测细胞生长。结果　MCF 7细胞ER为阳性 ,MCF 7/ADR细胞ER为阴性。成功构建真核细胞表达质粒 pCER ,转染MCF 7/ADR细胞 ,获得阳性克隆MTER/ADR。与对照组相比 ,MTER/ADR生长速度增快 ,S期细胞为 17.2 3 % (对照组为 14 .66% ) ,细胞对阿霉素的耐药性下降 ,阿霉素为 3mg/L时对细胞的抑制率为 45 % ,大于对照组细胞的抑制率 (为 2 4% ) ;且雌二醇 (E2 )能增加阿霉素对MTER/ADR细胞生长的抑制作用。结论　MCF 7/ADR乳腺癌耐药细胞的耐药性与其雌激素受体的表达缺失有一定关系。     

Personalized medicine for breast cancer: it is a new day!

Breast cancer remains the most common cancer diagnosed in women in the United States and is second only to lung cancer as a cause of cancer mortality. Breast cancer has become the prototypical solid tumor where targets have been identified within the tumor allowing for a personalized approach of systemic therapy.     

乳腺癌组织中HER2、ERα、ERβ、PR的表达及其相关性分析

目的探讨雌激素受体α（ERα）、雌激素受体β（ERβ）、孕激素受体（PR）、人类表皮生长因子受体2（HER2）在乳腺癌组织中的表达及其与TNM分期和腋窝淋巴结状况的关系。方法随机选择我院在2004年12月至2007年12月收治的HER2高表达（＋＋＋）51例与无表达（-）53例乳腺浸润性导管癌病例，分别检测乳腺癌组织的ERα、ERβ、PR的表达水平，分析其与TNM分期、腋窝淋巴结转移等临床指标的相关性。结果104例乳腺癌患者，TNM分期为I期的占14．42％，Ⅱ期占62．50％，Ⅲ期占19．23％，Ⅳ期占3．85％；HER2阳性的淋巴结转移率为41．18％，HER2阴性的转移率为47．5％；ERα、ERβ、PR的阳性表达率分别为52．88％、63．46％、73．08％。ERβ与ERα、PR的表达呈正相关（P〈0．01），与HER2的表达负相关（P〈0．01）；ERα与PR的表达正相关（P〈0．01），与HER2负相关（P〈0．01），PR与HER2的表达负相关（P〈0．05）；ERα、ERβ、PR、HER2的表达与淋巴结转移情况及TNM分期无显著相关性。结论HER2作为乳腺癌预后不良的重要指标与作为乳腺癌预后良好的重要指标ERα、ERβ、PR的表达呈负相关，与TNM分期及腋窝淋巴结转移状态未显示明显相关性。     

The pure antiandrogen ru 23908 (anandron®), a candidate of choice for the combined antihormonal treatment of prostatic cancer: A review

The nonsteroidal antiandrogen RU 23908 (Anandron^R) weakly interacts with the prostatic cytosolic androgen receptor and shows a fast dissociation rate. When administered to immature castrated rats up to the daily dose of 100 mg/kg, it is devoid of any androgenic activity but efficiently blocks the growth-promoting activity of androgens on ventral prostate and seminal vesicle weight, thus showing the characteristics of a pure antiandrogen. In intact animals, on the other hand, the antiandrogen administered alone exerts only a partial inhibition of prostate and seminal vesicle weight. This is due to the property of the pure antiandrogen to neutralize the inhibitory feedback effect of androgens at the pituitary level on the LH responsiveness to LHRH, as illustrated in vitro in rat anterior pituitary cells in culture as well as in vivo in intact and castrated animals. In intact animals, neutralization of the inhibitory feedback action of endogenous androgens leads to an increased LH and testosterone secretion, which partly overcomes the direct action of the antiandrogen at the level of the prostate and seminal vesicles. In fact, the plasma testosterone concentration is more than doubled 6 hr after the administration of 10 mg of RU 23908 while plasma LH and testosterone levels are increased by 7- and 17-fold, respectively, after 14 days of similar daily treatment. Efficient neutralization of the androgenic action at the prostatic level in intact animals thus requires prevention of this escape phenomenon through inhibition of LH secretion. Although inhibition of LH release can be achieved by estrogen and progestins, an optimal inhibitory effect on the prostate is obtained by the combined administration of the antiandrogen with an LHRH agonist that causes a specific blockage of testicular androgen biosynthesis as well as an inhibition of the LH responsiveness to LHRH.     

Vitamin D3对乳腺癌荷瘤裸鼠的治疗研究

目的 探讨维生素D3(vitamin D3，VitD3)对乳腺癌裸鼠移植模型的治疗作用。方法 裸鼠皮下接种MCF-7乳腺癌细胞，建立乳腺癌裸鼠移植模型。用VitD3和三苯氧胺(tamoxifen，TAM)给荷瘤裸鼠用药。用药4周后，检测肿块大小、血清钙、磷水平，并用流式细胞仪检测细胞凋亡和细胞周期。结果 VitD3治疗组血清钙水平高于对照组，血磷水平低于对照组，VitD3使肿瘤细胞凋亡增加，并使细胞停留在G0／G1期，与TAM有协同作用。结论 VitD3和TAM可明显诱导乳腺癌细胞凋亡，并阻滞细胞停留在G0／G1期。     

Co-targeting estrogen receptor and HER2 pathways in breast cancer

The estrogen steroid hormone receptor (ER) and human epithelial growth factor receptor 2 membrane tyrosine kinase growth factor receptor (HER2) are the mediators of two key pathways involved in breast carcinogenesis, invasive behavior and cell growth. Co-expression of these receptors results in specific biological features that are not fully understood, but include relative resistance to hormonal therapy and chemotherapy as well as better long-term outcome imparted by ER and worse outcome by HER2 expression. The ER and HER2 signaling pathways interact with each other as do many biological networks, and this creates opportunities for therapeutic co-targeting with agents that modulate these respective pathways. However, relatively few studies have been conducted to test concurrent manipulation of ER and HER2. The avoidance of chemotherapy side effects is an attractive feature that has further spurred explorations in this strategy. Still, the only dually targeted strategy approved by some regulatory agencies is the combination of hormonal therapy using aromatase inhibition and the HER2 kinase inhibitor lapatinib. Other dual combinations have also demonstrated a benefit, although most of the testing has compared hormonal therapy with or without HER2-directed agents and not the other way around, limiting the applicability of this concept in routine clinical practice, especially when chemotherapy is also used. Newer generation signal transduction inhibitors can augment the efficacy of hormonal therapy, with one such example of mTOR blockade using everolimus now in the clinic. The logical extension of ER and HER2 co-targeting is the discovery and clinical testing of “synthetic lethal” combinations attacking diverse pathways that produce quantum improvements over either therapy alone. Molecular annotation of human cancers can further inform personalized combinatorial regimens based on the unique circuitry of an individual patient's tumor, with the potential to yield much more than incremental gains in survival.     

Estrogen Replacement Therapy and Breast Cancer: Analysis of Age of Onset and Tumor Characteristics

Background: The use of exogenous estrogen has been scrutinized as a risk factor for breast cancer formation. This prospective study addresses the relationship between the use of estrogen replacement therapy and the age of onset of breast cancer. In addition, an analysis of differences in pathological features of breast cancer between estrogen users and non-estrogen-users was evaluated.Methods: A total of 425 women (age, 50 years) were evaluated during a 4-year period (1994–1997). Data, including the age at diagnosis, method of detection, family history, use of estrogen therapy, and tumor ploidy, S-phase fraction, histological category, estrogen receptor positivity, and grade, were prospectively collected. Data from a control group of 657 women without a diagnosis of breast cancer were obtained from the Evanston Northwestern division of the Womens Health Initiative. Significant associations between the use of estrogen and pathological parameters were determined using the ² test and t-test (P < .05).Results: At the time of breast cancer diagnosis, 140 patients were currently receiving estrogen and 202 patients had no history of estrogen use. Eighty-three patients were excluded from analysis (76 patients had a history of previous but not current use of estrogen therapy, four women used only progesterone, and three patients provided incomplete information). There was no difference between patients with breast cancer using estrogen at the time of diagnosis and those with no history of estrogen use with respect to tumor size, age of menopause, family history, mammographic sensitivity, axillary lymph node status, and histological features. Women using estrogen at the time of diagnosis were younger at the time of breast cancer diagnosis, by an average of 5.1 years (61.3 years vs. 66.4 years, P < .001). Women without a history of breast cancer who were receiving estrogen therapy were an average of 2.4 years younger (63.3 years vs. 65.7 years, P < .001) than women without a history of breast cancer who were not receiving estrogen therapy. Patients with breast cancer receiving estrogen also tended to have more grade II tumors (45.9% vs. 36.5%, P = .045) and fewer grade III tumors (25.6% vs. 37.0%, P =.015), compared with women not receiving estrogen therapy at the time of their diagnoses. Estrogen receptor positivity was noted to be more frequent for estrogen users presenting with lobular carcinoma (85% vs. 76%, P =.042) and less frequent for estrogen users presenting with ductal carcinoma (72% vs. 85%, P = .003).Conclusions: A significantly earlier age of diagnosis for women receiving estrogen therapy suggests that exogenous estrogen may accelerate the pathogenesis of postmenopausal breast cancer. Estrogen therapy may also play a role in altering the grade and estrogen receptor positivity for certain histological types of breast cancer.Presented at the 51st Annual Cancer Symposium of The Society of Surgical Oncology, San Digeo, California, March 26–29, 1998.     

The discrepancy between immunocytochemical and biochemical assay of estrogen receptor in breast cancer patients treated by endocrine therapy

Estrogen receptor (ER) expression was investigated by ER-immunocytochemical assay (ICA) and the dextran coated charcoal (DCC) method in 10 recurrent or primary-advanced breast cancer patients treated with endocrine or chmmo-endocrine therapy. In 6 of these 10 patients, ER was examined both before and after treatments by the 2 methods. ER contents measured by the DCC method were found to be decreased after treatments, however, no change in the immunoreactivities of ER-ICA was observed. In the remaining 4 patients, the ER of new lesions refractory to endocrine or chemo-endocrine therapy was examined. ER status was determined as negative in 3 of the 4 patients by the DCC method, whereas by ER-ICA, the proportion of ER stained cells was about 70 per cent, those cells being diffusely distributed in the section. A discrepancy between ER-ICA and the DCC method was thus demonstrated in breast cancer patients treated by endocrine therapy.     

Noncompliance with adjuvant radiation, chemotherapy, or hormonal therapy in breast cancer patients

INTRODUCTION: There is little information on patient-driven noncompliance of adjuvant therapies and its consequences. METHODS: This retrospective study compares clinical, pathological features and outcomes of breast cancer patients who were compliant to recommended radiation, chemotherapy, and hormonal therapies to those who were noncompliant. RESULTS: Noncompliance rates for chemotherapy, radiation, and tamoxifen were 31 of 421 (7%), 30 of 855 (4%), and 294 of (37%) respectively. Old age was associated with noncompliance to chemotherapy and radiation, but younger women tend to be more often noncompliant to tamoxifen. Noncompliance with chemotherapy or radiation did not significantly affect 5-year local and distant disease-free survival rates. Noncompliance with tamoxifen was associated with decreased 5-year local and distant disease-free survivals (87% versus 96%, 76% versus 87%, respectively, P < .001). CONCLUSION: Noncompliance with tamoxifen is the most common, resulting in significantly increased risk of local and distant disease recurrence.     

Apparent beneficial effects of tamoxifen on bone mineral content in patients with breast cancer: Preliminary study

Eight postmenopausal women undergoing adjuvant treatment with tamoxifen (20 mg/day) for breast cancer had baseline pretreatment, and 6-and 12-month post-treatment dual-photon determinations of vertebral bone mineral content (BMC). BMC measured at 6 and 12 months increased over baseline in all subjects. These observations imply that women treated with tamoxifen may retain rather than surrender the protective effect of estrogen against osteoporosis.