Targeting autophagy in breast cancer

Macroautophagy (referred to as autophagy here) is an intracellular degradation pathway enhanced in response to a variety of stresses and in response to nutrient deprivation. This process provides the cell with nutrients and energy by degrading aggregated and damaged proteins as well as compromised organelles. Since autophagy has been linked to diverse diseases including cancer, it has recently become a very interesting target in breast cancer treatment. Indeed, current clinical trials are trying to use chloroquine or hydroxychloroquine, alone or in combination with other drugs to inhibit autophagy during breast cancer therapy since chemotherapy and radiation, regimens that are used to treat breast cancer, are known to induce autophagy in cancer cells. Importantly, in breast cancer, autophagy has been involved in the development of resistance to chemotherapy and to anti-estrogens. Moreover, a close relationship has recently been described between autophagy and the HER2 receptor. Here, we discuss some of the recent findings relating autophagy and cancer with a particular focus on breast cancer therapy.     

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...     

Triple negative breast cancer compared to hormone receptor negative/HER2 positive breast cancer

The aim of this study is to reveal likely demographic, clinical, and pathological differences among hormone receptor negative breast cancer patients according to their HER-2 status. The medical records of hormone receptor negative breast cancer patients with known HER-2 status between January 1999 and December 2006 were reviewed, retrospectively. A total of 91 cases were included in the study (68 HER-2 negative cases and 23 HER-2 positive cases). The results obtained showed that median age, menarche age, childbearing age, number of children, menopause age, and body-mass indexes were similar in both groups. The HER-2 negative patients had more family history of breast cancer than HER-2 positive patients (13.2% and 0%, respectively, P = 0.091). Eighty-three patients received neoadjuvant/adjuvant chemotherapy. Recurrence occurred in 41 (46.6%) patients. Neither recurrence nor disease-free survival of those patients was associated with HER-2 status. Tumor size (P = 0.042) and number of involved lymph nodes (P = 0.001) were found to be independent prognostic factors for disease-free survival. A tendency for more frequent cerebral metastasis was found in HER-2 positive advanced stage patients (P = 0.052). HER-2 positive patients were less responsive to taxanes (P = 0.071). The number of involved lymph nodes (P = 0.004) and HER-2 status (P = 0.043) were found to be prognostic factors for overall survival. HER-2 positive and negative patients should be followed and treated with different strategies. HER-2 positive patients are at least as resistant to systemic therapies as the HER-2 negative patients. Genetic counseling should be routinely provided to triple negative patients and their families. HER-2 positive patients may be candidates for prophylactic treatment strategies concerning cerebral metastasis.     

Relation of serum levels of estrogen and dehydroepiandrosterone sulfate to hormone receptor status among postmenopausal women with breast cancer

Background: It is hypothesized that breast cancer may consist of heterogeneous diseases with different hormonal environments classified by hormone receptor status. Epidemiologic studies evaluating risk factors for breast cancer by hormone receptor status have supported the hypothesis. However, there are inconsistencies in the risk factor profiles by estrogen receptor (ER) and progesterone receptor (PR) across the studies. To clarify the heterogeneity of the disease, it is necessary to understand not only risk factor profiles but also the biologic characteristics such as the relationships among endogenous sex hormone levels and hormone receptors. Methods: We measured serum levels of estrone (E1), estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) in 142 postmenopausal women aged 50 and over with primary breast cancer who had undergone surgical treatment, and investigated the heterogeneity in the relations of endogenous sex hormone levels to hormone receptor status, using the case-series study method. Subjects were categorized into 3 classes based on tertiles of each hormone level in receptor-negative subjects, and odds ratios (ORs) for receptor-positive status compared with receptor-negative status were computed, taking the lowest category as a reference category. Results: There were clear trends toward higher serum levels of E1, E2, and DHEAS in women with PR+ cancer. The case-series approach revealed that PR+ status might be strongly associated with serum sex hormone levels. In particular, the OR of PR+ was large for a high DHEAS level (OR for the highest category = 4.28). No significant association between serum hormone levels and ER status was observed. Conclusion: The association of serum sex hormone levels with hormone receptor status may differ by PR status, but not by ER status. This finding suggests that PR status may be related to the heterogeneity in hormonal environments associated with breast cancer risk.     

Intake of fruits, and vegetables in relation to breast cancer risk by hormone receptor status

Summary The inconsistent associations between fruit and vegetable intake and breast cancer risk may be due to heterogeneity of associations by estrogen (ER) and progesterone receptor (PR) status of the tumors. We evaluated this hypothesis in a large (2,386 cases and 2,503 controls) population-based case-control study in Poland, conducted between 2000 and 2003. We observed significant associations between reduced overall risk of breast cancer and increasing levels of total fruit intake (odds ratio (OR) for highest versus lowest quartile = 0.76, 95%CI = 0.63–0.91; p-trend = 0.01), but not for total vegetable intake (1.13 (0.93–1.37), p-trend = 0.25), after controlling for age, energy intake and known risk factors for breast cancer. The inverse association with total fruit intake was stronger for risk of ER+ (0.69 (0.54–0.88), p-trend = 0.01) than ER− tumors (0.89 (0.67–1.19), p-trend = 0.57) (p-heterogeneity = 0.02). In conclusion, this study suggests that fruit intake might have differential associations for breast tumor subtypes defined by ER status.     

Glucocorticoid receptor expression in breast cancer associates with older patient age

Breast cancer can be classified according to estrogen (ER), progesterone (PR), and HER2 receptor expression. Recent evidence suggests that activation of the glucocorticoid receptor (GR) contributes to breast cell survival, although the incidence of GR expression in primary human breast tumors is not well established. We therefore evaluated ER, PR, HER2, and GR by immunohistochemistry from 231 patients and found that while African American (AA) patient tumors were much more likely to be ER negative compared to tumors from non-AA patients, GR expression was significantly higher in tumors from patients ≥50 regardless of ancestry. Prospective examination of GR expression in tumors should be considered to determine whether GR contributes to long-term clinical outcome.     

单激素受体阳性乳腺癌患者的临床病理特征及预后因素分析

目的分析雌激素或孕激素受体阳性即单激素受体阳性乳腺癌患者的临床病理特征及预后因素,比较两种单激素受体阳性即ER单阳性和PR单阳性乳腺癌患者的不同之处。方法2000年9月至2002年9月在我院就诊的Ⅰ～Ⅲ。期单激素受体阳性乳腺癌患者共112例,分析其临床病理特征及预后因素。结果全组患者5年生存率（OS）为89．0％,5年无病生存率（DFS）为79．8％。COX多因素预后分析显示,腋窝淋巴结转移数目是全组患者的独立预后因素（P=0．003）,脉管瘤栓是淋巴结阴性单激素受体阳性患者DFS的独立预后因素（P=0．038）。PR单阳性组年龄≤50岁（P=0．021）以及绝经前患者（P=0．033）显著多于ER单阳性组。PR单阳性组分级3级、肿瘤直径〉2cm、脉管瘤栓者的比例略高于ER单阳性组,但无统计学意义。内分泌治疗可显著改善ER单阳性组患者的OS（P=0．04）及DFS（P=0．000）。内分泌治疗有一定程度上提高了PR单阳性组患者的OS（P=0．271）及DFS（P=0．387）。结论腋窝淋巴结转移数目是全组患者的独立预后因素。内分泌治疗可显著改善ER单阳性组患者的生存,有改善PR单阳性组患者生存的趋势。     

Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer

BACKGROUND: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer has been emphasized, however, there is no general agreement as to how immunohistochemical assays should be evaluated. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. METHODS: Estrogen receptor (ER) and progesterone receptor (PgR) expression was examined by immunohistochemistry using Allred's score for primary breast tumors from 75 metastatic breast cancer patients who received first-line treatment with endocrine therapy (56 patients received tamoxifen, 11 patients received aromatase inhibitors, and 8 patients received LH-RH agonist or other endocrine reagents) on relapse. Correlation between hormone receptor status and response to endocrine therapy as well as post-relapse survival was analyzed. RESULTS: The most significant correlation between positive ER expression and response to any endocrine therapy (p = 0.011) or tamoxifen only (p = 0.030) occurred when the cutoff score was set at 10%. When the evaluation was based on Allred's score (TS), a cutoff point of TS>or=4 showed a more significant association between positive ER expression and response to all kinds of endocrine therapy (p = 0.020) or tamoxifen only (p = 0.047). When evaluated at a cutoff point of 1% positive cells, there were fifteen patients with both ER- and PgR-negative tumors, and three patients (20.0%) responded to the therapy. Patients with 1% or more ER or PgR positive cells had better survival after relapse (p = 0.0005 and p = 0.0008, respectively). CONCLUSIONS: The proportion score alone might be enough to predict hormone responsiveness and post-relapse survival in metastatic breast cancer. The cutoff might be set low, for example 1%, especially for metastatic disease.     

Endothelial progenitor cells in breast cancer patients

Purpose Development of new capillary blood vessels is essential for the growth of cancer. Two distinct processes, vasculogenesis and angiogenesis implement the formation of the new vascular network. Recently, it was demonstrated that vasculogenesis creates the primary network of vascular endothelial cells that will become major blood vessels in malignant tumors by the recruitment of CD34⁺/vascular endothelial growth factor receptor 2 (FLK-1)⁺ endothelial progenitor cells (EPCs) to sites of the new vessel formation with subsequent differentiation into mature endothelial cell. Therefore the aim of this study was a) to quantitate EPCs in breast cancer patients and b) to evaluate if the release of EPCs into the circulation is mainly regulated by the tumor himself. Experimental design CD34⁺FLK-1⁺ EPCs were measured in the peripheral circulation of patients with breast cancer (n = 47) before and after therapy. Furthermore the potential of EPCs to differentiate into endothelial cells was investigated by late-outgrowth experiments and the metabolic uptake of dil-acetylated-LDL and immunoreactivity against von Willebrand factor. Results In breast cancer patients the amount of CD34⁺FLK-1⁺ EPCs (percent of peripheral blood mononuclear cells) is significantly increased in women with breast cancer. Tumors larger than 2 cm showed significantly higher values of CD34⁺FLK-1⁺ EPCs. After excision of the tumor the amount of CD34⁺FLK-1⁺ EPCs rapidly declines. Conclusions Our findings lead to the tumor, as source of angiogenic chemokines, is most important for recruiting CD34⁺FLK-1⁺ EPCs during breast cancer development. Therefore circulating endothelial progenitor cells may work as a new diagnostic tool in the screening and diagnosis of breast cancer.     

Prognostic value of breast cancer subtypes on breast cancer specific survival, distant metastases and local relapse rates in conservatively managed early stage breast cancer: A retrospective clinical study

Aim

To ascertain if breast cancer subtypes had prognostic effect on breast cancer specific survival, distant metastases and local relapse rates in women affected by early stage breast cancer.

Patients and methods

Data of 774 patients affected by early stage breast cancer and treated with breast-conserving therapy were reviewed. Patients were grouped, based on steroid receptor status and HER2 status as: Luminal A (ER+/PR+/HER2−), Luminal B (ER+/PR+/HER2+), Basal-like (ER−/PR−/HER2−) and HER2 (ER−/PR−/HER2+). Distribution of variables among subtypes was evaluated with Pearson’s test. Survival rates were calculated with life tables; Cox regression stepwise method was used to identify predictive variables of survival.

Results

Median age was 55.0 years old (range 27–80) and median follow up time of 59.0 months (range 13.6–109.7). Breast cancer specific survival and distant metastases rates were different among breast cancer subtypes (both outcomes P = 0.00001) but there was no difference regarding local relapse rates (P = 0.07). Axillary nodes status (P = 0.00001), adjuvant therapy (P = 0.03) and breast cancer subtypes (P = 0.03) resulted prognostic factors of breast cancer specific survival; axillary node status (P = 0.00001) and breast cancer subtypes (P = 0.00001) had an impact on distant metastases. Age (P = 0.003), tumor size (P = 0.0001), positive or close surgical margin (P = 0.00001) and tumor grade 3 (P = 0.049) resulted prognostic factors of local relapse.

Conclusions

In our study, breast cancer subtype seems a prognostic factor of breast cancer specific survival and distant metastases rates, but not of local relapse rate. Patients could be submitted to conservative surgery, if feasible, but considering the differences in survivals, patients with worse prognosis should receive more aggressive adjuvant treatments.     

Prognostic significance of triple negative breast cancer at tumor size 1 cm and smaller

Aims

The purpose of this study was to clarify the prognostic significance of triple-negative breast cancer (TNBC) with a tumor size ≤ 1 cm.

Materials and methods

Patients with primary operable breast cancer with a tumor size ≤ 1 cm were enrolled at Changhua Christian Hospital and National Cheng-Kung University Hospital. Tumors negative for ER, PR, and HER-2 were classified as TNBCs and compared with tumors with any receptor positivity (non-TNBC) for disease-free survival (DFS) and cancer-specific survival (CSS).

Results

From 1995 to 2006, a total of 377 patients with tumor size ≤ 1 cm were enrolled. Compared with non-TNBC patients, TNBC patients with a tumor size ≤ 1 cm as a whole or in a lymph node-positive subgroup were not associated with a poorer 5-year DFS and CSS. In lymph node-negative patients (pT1a-bN0M0), TNBC was associated with a poorer 5-year CSS but not DFS. Compared with the hormone receptor-positive, HER-2-negative subgroup, TNBC was associated with poorer DFS and CSS. In the multivariate Cox regression hazard analysis, lymph node invasion was the most important cause of disease recurrence and cancer-specific death.

Conclusion

TNBC is very likely an independent risk factor in small (≤1 cm) node-negative invasive breast cancer. With tumors 1 cm and smaller, lymph node invasion was the single most important prognostic factor.     

Triple-negative subtype predicts poor overall survival and high locoregional relapse in inflammatory breast cancer

Background.

Numerous studies have demonstrated that expression of estrogen/progesterone receptor (ER/PR) and human epidermal growth factor receptor (HER)-2 is important for predicting overall survival (OS), distant relapse (DR), and locoregional relapse (LRR) in early and advanced breast cancer patients. However, these findings have not been confirmed for inflammatory breast cancer (IBC), which has different biological features than non-IBC.

Methods.

We retrospectively analyzed the records of 316 women who presented to MD Anderson Cancer Center in 1989–2008 with newly diagnosed IBC without distant metastases. Most patients received neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. Patients were grouped according to receptor status: ER⁺ (ER⁺/PR⁺ and HER-2−; n = 105), ER⁺HER-2⁺ (ER⁺/PR⁺ and HER-2⁺; n = 37), HER-2⁺ (ER⁻/PR⁻ and HER-2⁺; n = 83), or triple-negative (TN) (ER⁻PR⁻HER-2⁻; n = 91). Kaplan–Meier and Cox proportional hazards methods were used to assess LRR, DR, and OS rates and their associations with prognostic factors.

Results.

The median age was 50 years (range, 24–83 years). The median follow-up time and median OS time for all patients were both 33 months. The 5-year actuarial OS rates were 58.7% for the entire cohort, 69.7% for ER⁺ patients, 73.5% for ER⁺HER-2⁺ patients, 54.0% for HER=2⁺ patients, and 42.7% for TN patients (p < .0001); 5-year LRR rates were 20.3%, 8.0%, 12.6%, 22.6%, and 38.6%, respectively, for the four subgroups (p < .0001); and 5-year DR rates were 45.5%, 28.8%, 50.1%, 52.1%, and 56.7%, respectively (p < .001). OS and LRR rates were worse for TN patients than for any other subgroup (p < .0001–.03).

Conclusions.

TN disease is associated with worse OS, DR, and LRR outcomes in IBC patients, indicating the need for developing new locoregional and systemic treatment strategies for patients with this aggressive subtype.     

Clinical impact of assay of estrogen receptor beta cx in breast cancer

Since 1996 when estrogen receptor beta(ER beta) was discovered, much effort has been devoted to the question of the value of ER beta as a prognostic and/or predictive factor in breast cancer and its potential as a novel target for pharmacological intervention. When estrogen receptors are applied on sucrose gradients and quantified by ligand binding, we found that in contrast to ER alpha, which has a narrow tissue distribution, ER beta is expressed in many tissues including both normal and malignant breast tissue. Receptor protein levels in tissues can also be measured from the intensities of bands after Western blotting and can be quantified when purified and quantified receptor is used as a standard. With this technique, we found that there were some tumors which had over 600 fmol/mg of ER beta protein but no detectable estradiol binding. In such tumors, RT-PCR analysis revealed that ER beta cx is the only ER beta isoform present. ER beta cx is a splice variant which utilizes an alternative exon 8. This change in the C-terminus results in very poor binding to estradiol (E2) and has a dominant negative effect on ER alpha function. Immunohistochemical analysis with an ER beta cx specific antibody in 115 ER alpha-positive breast cancers revealed that about half of the samples expressed ER beta cx protein. Initial analysis of samples from patients with preoperative tamoxifen treatment revealed that ER alpha-positive tumors expressing ER beta cx and lacking PR seemed to be resistant to the anti-estrogen. We conclude that, in order to better characterize breast cancers and design appropriate therapy for individual patients, assays for ER beta cx must be made available to clinicians.     

三阴性乳腺癌患者中FOXA1与雌激素受体β的表达及其相关性研究

背景与目的：研究显示雌激素受体β(estrogen receptor beta,ERβ)在三阴性乳腺癌(triple negative breast cancer,TNBC)中的表达与TNBC患者的预后可能存在正相关,而ERβ和雌激素受体α(estrogen receptor alpha,ERα)存在高度同源性,ERα的表达和活性与叉头框蛋白A1(fork head box protein A1,FOXA1)密切相关。该研究旨在分析FOXA1和ERβ在TNBC中的表达情况及其与临床病理指标及预后的相关性。方法：收集2011年11月—2013年12月北京协和医院乳腺癌标本,根据ERα、孕激素受体(progesterone receptor,PR)和人表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)的表达情况,筛选出TNBC。根据ERβ表达,随机选取ERβ阳性和阴性的乳腺癌标本各30例,应用免疫组化检测样本中FOXA1表达情况。由于染色不佳及飞片等原因,最终获得染色情况佳的标本共48例(ERβ阴性20例,ERβ阳性28例)。比较TNBC中FOXA1及ERβ表达的相关性及其与各临床病理指标及预后之间的关系。结果：FOXA1总体阳性率为35.4%(17/48),其中ERβ阳性组FOXA1阳性率为35.7%(10/28),ERβ阴性组FOXA1阳性率为35%(7/20),两组差异无统计学意义(P=0.83),即FOXA1的表达与ERβ的表达无相关性。FOXA1阳性组与FOXA1阴性组的患者年龄、肿瘤大小、腋窝淋巴结转移数目、肿瘤分级、肿瘤分期、诺丁汉预后指数(Nottingham prognostic index,NPI)和无病生存率(disease free survival,DFS)差异均无统计学意义;两组Ki-67指数差异具有统计学意义(P<0.01),即在FOXA1阳性组中Ki-67指数显著低于FOXA1阴性组,两者呈负相关。结论：在TNBC中,FOXA1的表达与ERβ的表达差异无统计学意义,FOXA1的表达与Ki-67指数呈负相关,提示FOXA1阳性表达的三阴性乳腺癌细胞增殖性较低。     

乳腺癌雌激素受体孕激素受体和C-erbB-2癌基因蛋白表达的临床意义

目的研究乳腺癌中雌、孕激素受体(ER,PR)与C,erbB-2癌基因的表达情况及临床意义。方法应用免疫组化S.P法,对82例原发性乳腺癌组织进行了ER,PR和C/erbB02检测,并进行统计学分析。结果ER,PR和C1erbB22的表达率分别为54.9%,40.2%,47.6%。ER的表达与C3erbB42的表达呈显著负相关(P<0.01)。C5erbB62的表达与肿瘤体积呈显著正相关(P<0.01),与年龄、组织学类型和淋巴结转移无明显相关性(P>0.05)。结论ER,PR的阳性表达是乳腺癌预后良好的指标,C7erbB82是乳腺癌预后不良的指标。ER,PR和C9erbB:2的测定对乳腺癌的诊断、治疗和预后判断具有重要的指导意义。     

乳腺癌原发灶和转移灶激素受体与HER2表达差异及其影响因素

目的 乳腺癌的治疗已经进入分子分型时代,雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人类表皮生长因子受体-2(human epidermal growth factor receptor 2,HER2)的表达对指导制订乳腺癌治疗方案及评价患者预后等尤为重要.许多研究证实,部分乳腺癌患者原发灶及转移灶激素受体与HER2表达存在差异,影响术后辅助及解救治疗方案的制订,进而影响患者的治疗效果及预后.本研究探讨乳腺癌原发灶与腋窝及远处转移灶之间激素受体与HER2表达的差异及其临床意义,同时分析了造成差异的影响因素.方法 以乳腺癌、激素受体(ER和PR)、HER2、原发灶和转移灶为关键词,检索PubMed、CNKI数据库和万方数据库1995-01-2016-10的相关文献.共505篇文章被检索到.纳入标准:原发灶与腋窝转移灶激素受体及HER2表达差异情况,原发灶与远处转移灶激素受体及HER2表达差异情况,原发灶与转移灶激素受体及HER2表达差异情况的临床意义.根据纳入标准最终纳入分析38篇文献.结果 在部分乳腺癌患者中,原发灶与腋窝转移灶及远处转移灶激素受体及HER2表达情况存在差异,多数文献报道,乳腺癌原发灶与转移灶ER表达状况变化(阳性转阴性或阴性转阳性)比例约为20％,PR约为20％,HER2约为15％.“肿瘤异质性、抗肿瘤治疗和检测方法”等是影响其表达差异的影响因素.结论 推荐对于存在局部及远处转移的乳腺癌患者,同时检测并综合原发灶及转移灶的激素受体及HER2表达情况制订治疗方案.     

PGRMC1在激素治疗中促进乳腺癌细胞增殖的机制研究

目的 探讨孕激素受体膜组分1（progesterone receptor membrane components 1,PGRMC1）在激素治疗中促进乳腺癌细胞增殖的作用机制。 方法 雌激素受体（estrogen receptor,ER）阳性的乳腺癌MCF7细胞经雌孕激素处理后,用过表达PGRMC1、敲降ER抑制因子PHB1（shPHB1-1和shPHB1-2）及其相应阴性对照的慢病毒液进行感染。采用免疫共沉淀联合质谱分析及GST pull-down实验检测PGRMC1与PHB复合体（PHB1和PHB2）的相互作用,免疫印迹法和RT-qPCR检测PHB1、PHB2和PGRMC1的表达情况,CCK-8和EDU实验检测细胞的增殖能力,流式细胞术检测细胞周期情况,RT-qPCR检测ER信号通路下游靶基因THBS1、CXCL12和GREB1的表达情况。结果 免疫共沉淀联合质谱分析发现,PHB1和PHB2均存在于PGRMC1的免疫共沉淀组分中;GST pull-down鉴定体外条件下PGRMC1与PHB复合体存在直接相互作用。与相应对照组相比,过表达PGRMC1和下调PHB1的乳腺癌细胞增殖速度均明显加快（均P<0.05）,S期和G2/M期阳性细胞比例均明显增加（均P<0.05）,且能够显著促进ER信号通路下游靶基因THBS1、CXCL12和GREB1的表达（均P<0.01）。PGRMC1过表达后MCF7细胞中PHB1与ER的相互作用减弱。下调PHB1后再过表达PGRMC1的细胞周期中,S期和G2/M期阳性细胞比例与单独下调PHB1相比无明显变化（均P>0.05）。结论 PGRMC1可能通过与PHB复合体结合,并解除后者对ER信号通路的抑制作用,从而促进ER信号通路的活化和下游靶基因的表达,加速激素刺激条件下乳腺癌细胞的恶性增殖。     

CpG island methylation profile of estrogen receptor alpha in Iranian females with triple negative or non-triple negative breast cancer: new marker of poor prognosis

One decade early onset of the breast cancer in Iranian females was reported but the basis of the observed difference has remained unclear and difference in gene silencing by epigenetic processes is suggested. Hence, this study was sought to map the methylation status of ER gene CpG islands and its impact on clinicopathological factors of triple negative and non-triple negative ductal cell carcinoma of the breast in Iranian females. Surgically resected formalin-fixed paraffin-embedded breast tissues from sixty Iranian women with confirmed invasive ductal carcinoma were assessed by methylation-specific PCR using primer sets encompassing some of the 29 CpGs across the ER gene CpG island. The estrogen and progesterone receptors, Her-2 overexpression, and nuclear accumulation of P53 were examined using immunohistochemistry (IHC). Methylated ER3, ER4, and ER5 were found in 41.7, 11.3, and 43.3% of the samples, respectively. Significantly higher methylation of ER4 was found in the tumors with nuclear accumulation of P53, and significantly higher methylation of ER5 was found in patients with lymph node involvement and tumor with bigger size or higher grades. Furthermore, significantly higher rate of ER5 methylation was found in patients with Her-2+ tumors and in postmenopausal patients with ER-, PgR-, or ER-/PgR- tumors. However, no significant difference in ERs methylation status was found between triple negative and non-triple negative tumors in pre- and postmenopausal patients. Findings revealed that aberrant hypermethylation of ER-a gene frequently occur in Iranian women with invasive ductal cell carcinoma of the breast. However, methylation of different CpG islands produced a diverse impact on the prognosis of breast cancer, and ER5 was found to be the most frequently methylated region in the Iranian women, and could serve as a marker of poor prognosis.     

金属硫蛋白、雌激素受体和孕激素受体在乳腺癌中的表达及相关性研究

目的 探讨浸润性乳腺导管癌金属硫蛋白(MT)与雌激素受体(ER)、孕激素受体(PR)表达的意义及其相关性。方法 采用免疫组化法检测浸润性乳腺导管癌组织中MT及ER、PR表达的变化。结果MT及ER、PR在浸润性乳腺导管癌中阳性率分别为40.6％(26/64)、59.4％(38/64)和50.0％(32/64)。MT表达与乳腺癌病理分级有关(P<0.05);与有无淋巴结转移有关(P<0.05)。ER、PR表达率在MT阳性与阴性病例中有明显差异,分别为42.3％(11/26)、71.1％(27/38,P<0.05)和34.6％(9/26)、60.5％(23/38,P<0.05)。结论 乳腺癌MT表达与ER、PR表达呈明显负相关,MT有可能成为预测乳腺癌预后的指标之一。