基质细胞衍化因子-1的表达及其与乳腺癌患者预后的关系

目的探讨基质细胞衍化因子-1(SDF-1)在不同细胞系及乳腺癌组织和正常乳腺组织中的表达,并分析SDF-1的表达水平与乳腺癌患者预后的关系。方法选择乳腺癌细胞系、成纤维细胞系、血管内皮细胞系,利用RT-PCR方法分析SDF-1mRNA的表达。采用免疫组织化学染色和实时定量PCR测定120例乳腺癌组织和32例正常乳腺组织中SDF-1的表达。通过SPSS统计软件对所得结果行统计学分析。结果SDF-1的表达见于人胚胎肺成纤维细胞系、某些乳腺癌细胞系(MDA-MB435s、MDA-MB436、MCF7)及乳腺癌和正常乳腺组织。淋巴结有转移者SDF-1mRNA的表达水平为399.00±210.00,淋巴结无转移者为0.89±0.47(P=0.048)。预后不良者(出现肿瘤局部复发、远处转移和因乳腺癌死亡者)较无疾病存活者SDF-1mRNA水平明显增高,为670.00±346.00vs0.83±0.35(P=0.01)。SDF-1mRNA的表达水平与患者的总存活率和无瘤存活率有关,P值分别为0.01和0.035。结论SDF-1mRNA的表达既可见于基质细胞也可见于乳腺癌细胞。SDF-1的表达水平与乳腺癌患者有无淋巴结转移、预后和存活密切相关。SDF-1可作为乳腺癌患者预后判断的一项指标。     

超声引导空芯针穿刺活检诊断乳腺癌激素受体状态的价值

目的探讨超声引导空芯针穿刺活检(ultrasound-guided core needle biopsy,US-CNB)检测乳腺癌激素受体状态的准确性。方法回顾性分析2016年9月~2019年4月127例未经过新辅助治疗的131个乳腺癌病灶。US-CNB后7~46 d行乳腺癌手术。对比US-CNB和手术切除组织的病理结果,包括雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)。结果US-CNB均顺利完成。US-CNB标本中ER阳性、阴性病灶分别为121个(121/131,92.4%)和10个(10/131,7.6%),术后标本中分别为120个(120/131,91.6%)和11个(11/131,8.4%)(McNemar检验P=1.000),两者诊断一致率为99.2%(130/131)(κ=0.948,P=0.000)。US-CNB标本中PR阳性、阴性病灶分别为106个(80.9%,106/131)和25个(19.1%,25/131),术后标本中分别为106个(80.9%,106/131)和25个(19.1%,25/131)(McNemar检验P=1.000),两者诊断一致率为95.4%(125/131)(κ=0.852,P=0.000)。US-CNB与手术标本ER、PR表达性质均无统计学差异(McNemar检验P=1.000)。在表达比例方面,US-CNB与手术标本ER阳性细胞所占比例差异无统计学意义[中位数90%(70%~90%)vs.90%(80%~90%),Wilcoxon检验,Z=-1.804,P=0.071]。US-CNB与手术标本PR阳性细胞所占比例差异无统计学意义[中位数60%(5%~90%)vs.60%(5%~90%),Wilcoxon检验,Z=-0.592,P=0.554]。US-CNB与手术标本ER、PR表达强弱差异无统计学意义(Wilcoxon检验,Z=-0.786、P=0.432;Z=-1.792,P=0.073)。结论US-CNB可准确评价乳腺癌雌、孕激素受体表达状态,是术前评估乳腺癌激素受体表达的可靠方法。     

IGF and Insulin Receptor Signaling in Breast Cancer

Major molecular abnormalities in breast cancer include the deregulation of several components of the IGF system. It is well recognized that the epithelial breast cancer cells commonly overexpress the IGF-I receptor while IGF-II is expressed by the tumor stroma. In view to the fact that the IGF-IR has mitogenic, pro-invasive and anti-apoptotic effects and mediates resistance to a variety of anti-cancer therapies, breast cancer is expected to be a candidate to therapeutic approaches aimed to inhibit the IGF-IR. However, there is increasing awareness that IGF system in cancer undergoes signal diversification by various mechanisms. One of these mechanisms is the aberrant expression of insulin receptor (IR) isoform A (IR-A), which is a high affinity receptor for both insulin and IGF-II, in breast cancer cells. Moreover, overexpression of both IGF-IR and IR-A in breast cancer cells, leads to overexpression of hybrid IR/IGF-IR receptors (HRs) as well. Upon binding to IGF-II, both IR-A and HRs may activate unique signaling patterns, which predominantly mediate proliferative effects. A better understanding of IGF system signal diversification in breast cancer has important implications for cancer prevention measures, which should include control of insulin resistance and associated hyperinsulinemia. Moreover, in addition to the IGF-IR, both IR-A and HRs should be also considered as molecular targets for anti-cancer therapies. Grant support: This work was partially supported by grants from the AIRC (Associazione Italiana per la Ricerca sul Cancro) and PRIN-MIUR 2005 (Ministero Italiano Università e Ricerca) to A.B.     

不同分子亚型乳腺癌中程序性细胞死亡4的表达及其与预后的关系

目的探讨不同分子亚型乳腺癌中程序性细胞死亡4（PDCD4）的表达及其与预后的关系。方法收集广东省妇幼保健院乳腺科2007年1月至2009年12月期间手术切除的乳腺癌及相应的癌旁组织标本各338例,按免疫表型将其分为管腔型（199例）、HER-2阳性型（63例）及三阴型（76例）,采用SP法检测不同分子亚型乳腺癌中PDCD4的表达情况,并分析其与预后的关系。用SPSS13．0软件进行统计学分析,率的比较用卡方检验。用Kaplan-Meier法对患者的无病生存及总生存情况进行分析,用log-rank检验比较生存曲线间的差异,运用Cox分析影响各分子亚型乳腺癌生存预后的因素。结果①338例乳腺癌中PDCD4蛋白表达总阳性率为56．80％（192／338）,表达缺失率为43．20％（146／338）;相应癌旁正常乳腺组织中PDCD4蛋白表达总阳性率为96．44％（326／338）。其中管腔型乳腺癌中PDCD4表达阳性率明显高于HER-2阳性型（χ2=38．315,P=0．000）及三阴型（χ2=33．746,P=0．000）,而HER-2阳性型及三阴型乳腺癌中PDCD4蛋白表达阳性率差异无统计学意义（χ2=0．448,P=0．503）;且管腔型、HER-2阳性型及三阴型乳腺癌中PDCD4蛋白表达阳性率均分别明显低于癌旁正常组织（χ2=39．206,P=0．000;χ2-60．398,P=0．000;χ2=65．185,P=0．000）。②管腔型乳腺癌中PDCD4表达与年龄、组织学分级、T分期及N分期均有关（χ2=3．979,P=0．046;22：13．826,P=0．001;χ2=12．604,P=0．002;χ2=28．613,P=0．000）;HER-2阳性型乳腺癌中PDCD4表达与年龄及T分期无关（χ2=0．033,P=0．856;χ2=4．258,P=0．119）,而与组织学分级及N分期有关（χ2=9．972,P=0．007;χ2=13．714,P=0．003）;三阴型乳腺癌中PDCD4表达与年龄及T分期无关（χ2=0．817,P=0．366;χ2=0．990,P=0．610）,而与组织学分级及N分期有关（χ2=14．269,P=-0．001;χ2=7．945,P=0．047）。③338例乳腺癌中PDCD4蛋白阳性表达者其无病生存及总生存均明显优于PDCD4蛋白阴性表达者（P=0．000,P=0．000）,且在各分子亚型乳腺癌中,同样显示出PDCD4蛋白阳性表达者其无病生存及总生存明显优于PDCD4蛋白阴性表达者（P=0．000,P=0．000）。④多因素分析显示,影响乳腺癌无病生存的独立因素包括T分期、N分期及PDCD4表达（P=0．004,P=0．001,P=0．000）,影响乳腺癌总生存的独立因素包括组织学分级、T分期、N分期及PDCD4表达。结论PDCD4在乳腺癌中表达下调,其中三阴型及HER-2阳性型乳腺癌中下调更明显;PDCD4蛋白阳性表达者无病生存及总生存均明显优于PDCD4蛋白阴性表达者,PDCD4可作为预测乳腺癌预后的独立因素。     

Crosstalk Between IGF1R and Estrogen Receptor Signaling in Breast Cancer

After the discovery that depriving certain breast tumors of estrogen promoted tumor regression, therapeutic strategies aimed at depriving tumors of this hormone were developed. The tumorigenic properties of estrogen are regulated through the estrogen receptor-α (ER), making understanding the mechanisms that activate this receptor highly relevant. In addition to estrogen activating the ER, other growth factor pathways, such as the insulin-like growth factors (IGFs), can activate the ER. This review will examine the interaction between these two pathways. Estrogen can activate the growth stimulatory properties of the IGF pathway via ER’s genomic and non-genomic functions. Further, blockade of ER function can inhibit IGF-mediated mitogenesis and blocking IGF action can inhibit estrogen stimulation of breast cancer cells. Collectively, these observations suggest that the two growth regulatory pathways are tightly linked and a more thorough understanding of the mechanism of this crosstalk could lead to improved therapeutic strategies in breast cancer.     

Regulation of Prolactin Receptor Levels and Activity in Breast Cancer

From its traditional identity as a hormone involved in growth and differentiation of mammary epithelium and in lactation, to having a pertinent role in the development of mammary carcinoma, the peptide hormone/cytokine prolactin (PRL) has emerged as a versatile signaling molecule. There has been significant progress in our understanding of the fine working of PRL in the past several years. Notably, much effort has been concentrated on the mediator of PRL action, namely, the prolactin receptor (PRLr). The causal link between increased PRLr expression and breast cancer is being increasingly appreciated. Considering that the level of the receptor on the surface is a critical determinant of signaling output in response to PRL, the uncovering of regulatory elements that control receptor expression becomes important. The principle focus of this review is on the regulation of PRLr expression and activity in breast cancer with a brief overview of different isoforms of PRLr, their expression, signaling capabilities and the biological outcomes of PRL/PRLr signaling.     

CyclinD1在不同分子亚型乳腺癌中的表达及其对预后的影响

目的检测cyclinD1在不同分子亚型乳腺癌中的表达,分析其表达与临床病理特征和预后的关系。方法采用免疫组织化学法检测175例乳腺癌组织标本中cyclinD1的表达情况,应用卡方检验分析cyclinD1在不同分子亚型乳腺癌中的表达,采用Spearman秩相关方法分析cyclinD1表达与临床病理特征的相关性,运用Kaplan．Meier生存曲线分析cyclinD1不同表达对预后的影响。结果①CyclinD1阳性表达在LuminalA型所占比例最高（P〈0．05）,而cyclinDI阴性表达在LuminalB型所占比例最高（P〈0．05）。②CyclinD1阳性表达与临床分期、组织学分级及PR无关（P〉0．05）,与淋巴结转移数目（rs=0．197,P〈0．01）、ER呈正相关（rs=0．139,P〈0．05）;cyclinD1阳性表达与Her-2呈负相关（rs=0．131,P〈0．05）。③CyclinD1阳性表达越强,无瘤生存时间越长（P〈0．05）。结论CyclinD1阳性表达与ER、Her-2及淋巴结转移数目有明显相关性,且其阳性表达提示相对良好的预后,可作为乳腺癌预后评估的参考指标。     

Hormone Receptor Status of Breast Cancer in the Himalayan Region of Northern India

The role of hormone receptors as a prognostic and therapeutic tool in breast cancer is widely accepted. The frequency of nonreactivity of estrogen and progesterone receptors in breast cancer patients of India is much more common than in the West. This study was conducted with the aim of analysis of steroid receptor status in breast cancer with clinico-pathological characteristics from the northern hilly state of Himachal Pradesh, India located in the region of the Western Himalayas. Fifty five consecutive patients with the diagnosis of breast cancer were included in this study. Detailed clinical and histopathologic data was recorded in all cases. Estrogen receptor and progesterone receptor status was evaluated by immunohistochemistry. Chi-square test was used for statistical analysis. On immunohistochemical staining, 34.5% cases proved to be estrogen receptor positive and 36.4% cases progesterone receptor positive. The results in the present study documented low estrogen receptor and progesterone receptor positivity in breast cancer from this region of India.     

Expression of Cathepsin B and Cystatin C in Human Breast Cancer

Cathepsin B, which was originally found to be a lysosomal cysteine protease, is also an important matrix protease. In this study, we investigated the expression of cathepsin B and cystatin C, the strongest inhibitor of cathepsin B, and measured the relative amounts of each in human breast cancer tissues. Cystatin C expression relative to cathepsin B expression was found to be decreased. This finding could be associated with the looseness of cancerous interstitial tissue, which might play a role in cancer invasion and metastasis. This report documents the first simultaneous investigation of cathepsin B and cystatin C in breast cancer tissues. Received: February 23, 2000 / Accepted: November 20, 2000     

The Prognostic Significance of Micrometastases in Breast Cancer: A SEER Population-Based Analysis

Introduction The prognostic significance of lymph node micrometastases in breast cancer is controversial. We hypothesized that the survival of patients with solely micrometastatic disease (N1mi) would be intermediate to patients with 1–3 tumor-positive lymph nodes (N1) and those with no positive lymph nodes (N0). Methods We queried the surveillance, epidemiology and end results (SEER) database for all patients between 1992 and 2003 with invasive ductal or lobular breast cancer without distant metastases and ≤3 axillary nodes with macroscopic disease. Patients were stratified by nodal involvement and compared using the Kaplan–Meier method. Cox proportional hazards regression was utilized to compare survival after adjusting for patient and tumor characteristics. Results Between 1992 and 2003, N1mi diagnoses increased from 2.3% to 7% among the 209,720 study patients (p < 0.001). In a T-stage stratified univariate analysis, N1mi patients had a worse prognosis in T2 lesions. On multivariate analysis, N1mi remained a significant prognostic indicator across all patients (p < 0.0001) with a hazard ratio of 1.35 compared to N0 disease and 0.82 compared to N1 disease. Other negative prognostic factors included male gender, estrogen-receptor negativity, progesterone-receptor negativity, lobular histology, higher grade, older age, higher T-stage, and diagnosis in an earlier time period. Conclusion Nodal micrometastasis of breast cancer carries a prognosis intermediate to N0 and N1 disease, even after adjusting for tumor- and patient-related factors. Prospective study is warranted and the results of pending trials are highly anticipated. Until then adjuvant therapy trials should consider using N1mi as a stratification factor when determining nodal status.     

CXCR4在乳腺癌中的表达及意义

目的：研究CXCR4在人乳腺癌及癌前病变中的表达情况,并分析其与乳腺癌相关临床病理指标之间的关系。方法：采用免疫组织化学方法（IHC）研究CXCR4在23例乳腺导管上皮增生,26例重度不典型导管上皮增生,34例乳腺导管内癌（DCIS）和126例浸润性乳腺癌组织中的表达差异情况;分析浸润性乳腺癌中CXCR4表达与腋窝淋巴结受累数目、临床分期、肿瘤直径、组织学分级等临床病理指标的相关性。结果：CXCR4在乳腺导管上皮增生、重度不典型导管上皮增生、乳腺导管内癌、浸润性乳腺癌组织中的阳性表达率依次为8.70%、23.08%、56.25%、60.32%,表达水平呈现增高趋势,具有随病变恶性程度加重而逐步增高的趋势（P〈0.05）;但导管内癌和浸润性乳腺癌两组表达水平无明显差别。CXCR4在浸润性乳腺癌中的表达与腋窝淋巴结受累数目、临床分期呈正相关,与肿瘤直径、组织学分级无明显相关性。淋巴结阳性组浸润性乳腺癌CX-CR4阳性表达率高于淋巴结阴性组（P〈0.05）。结论：CXCR4可能是乳腺癌发生的早期分子事件;CXCR4在浸润性乳腺癌中的表达与乳腺癌进展的临床病理指标相关,可作为乳腺癌的诊断指标;CXCR4可能成为乳腺癌治疗的新靶点。     

Genetic Prognostic Index Influences Patient Outcome for Node-Positive Breast Cancer

Purpose To establish a novel genetic prognostic index among node-positive breast cancer patients. Methods Using a cDNA microarray, the gene expression profiles of 20 primary breast cancers that had metastasis to four or more axillary lymph nodes were examined. Ten patients survived disease-free for more than 5 years (5S), while ten patients died of breast cancer within 5 years of surgery (5D). Results A set of genes characterizing each group was identified. Sixteen genes were underexpressed in 5D compared to 5S, and 15 genes were underexpressed in 5S in comparison to 5D. The prognostic index (PI) was established, which could predict the postoperative outcome with five genes that were commonly underexpressed in the 5D group; these genes encoded granulin (GRN), heat shock 90 kDa protein 1 beta (HSPCB), large tumor suppressor homolog 1 (LATS1), valosin-containing protein (VCP), and LIM-and-SH3 protein1 (LASP1). Conclusion These five genes might play an important role in deciding the behavior of node-positive breast cancer. The PI system could thus predict the prognosis of node-positive breast cancer, and might therefore be able to provide valuable information for the prognosis of breast cancer patients.     

A Significant Correlation between Nuclear CXCR4 Expression and Axillary Lymph Node Metastasis in Hormonal Receptor Negative Breast Cancer

Background and objectives In breast cancer, the expression pattern of CXCR4 may be correlated with the degree of axillary lymph node involvement. The aim of this study was to evaluate the contributing factors that contribute to the correlation between CXCR4 expression and axillary lymph node metastasis in breast cancer. Methods Between August 1997 and August 2002, sections of paraffin-embedded tissue were obtained from 107 patients who received optimal treatment for breast cancer. The expression of CXCR4 was evaluated by immunohistochemical staining. Results A significant correlation was found in the expression of nuclear CXCR4 and lymph node metastasis (P = 0.03). We found a significant correlation between a high nuclear expression of CXCR4 and axillary lymphatic metastasis in estrogen and progesterone receptor negative breast cancer (P = 0.01 and P = 0.01). There was a significant correlation between the high expression of nuclear CXCR4 and axillary lymphatic metastasis in comparisons between positive estrogen and/or progesterone receptor expression and negative expression (P = 0.02). Conclusions Our results showed that high expression of nuclear CXCR4 was significantly correlated with lymph node metastasis in breast cancer. The high expression of nuclear CXCR4 in hormone receptor negative breast cancer was associated with a high possibility of lymph node metastasis.     

Estrogen Receptor Alpha in Human Breast Cancer: Occurrence and Significance

Estrogens have long been recognized as being important for stimulating the growth of a large proportion of breast cancers. Now it is recognized that estrogen action is mediated by two receptors, and the presence of estrogen receptor (ER)³ correlates with better prognosis and the likelihood of response to hormonal therapy. Over half of all breast cancers overexpress ER and around 70% of these respond to anti-estrogen (for example tamoxifen) therapy. In addition, the presence of elevated levels of ER in benign breast epithelium appears to indicate an increased risk of breast cancer, suggesting a role for ER in breast cancer initiation, as well as progression. However, a proportion of ER-positive tumors does not respond to endocrine therapy and the majority of those that do respond eventually become resistant. Most resistant tumors remain ER-positive and frequently respond to alternative endocrine treatment, indicative of a continued role for ER in breast cancer cell proliferation. The problem of resistance has resulted in the search for and the development of diverse hormonal therapies designed to inhibit ER action, while research on the mechanisms which underlie resistance has shed light on the cellular mechanisms, other than ligand binding, which control ER function.     

Function of the IGF-I Receptor in Breast Cancer

The insulin-like growth factor-I receptor (IGF-IR)³ is a transmembrane tyrosine kinaseregulating various biological processes such as proliferation, survival, transformation, differentiation,cell-cell and cell-substrate interactions. Different signaling pathways may underlie thesepleiotropic effects. The specific pathways engaged depend on the number of activated IGF-IRs,availability of intracellular signal transducers, the action of negative regulators, and is influencedby extracellular modulators. Experimental and clinical data implicate the IGF-IR in breastcancer etiology. There is strong evidence linking hyperactivation of the IGF-IR with theearly stages of breast cancer. In primary breast tumors, the IGF-IR is overexpressed andhyperphosphorylated, which correlates with radio-resistance and tumor recurrence. In vitro,the IGF-IR is often required for mitogenesis and transformation, and its overexpression oractivation counteract effects of various pro-apoptotic treatments. In hormone-responsive breastcancer cells, IGF-IR function is strongly linked with estrogen receptor (ER) action. TheIGF-IR and the ER are co-expressed in breast tumors. Moreover, estrogens stimulate the expressionof the IGF-IR and its major signaling substrate IRS-1, while antiestrogens downregulateIGF-IR signaling, mainly by decreasing IRS-1 expression and function. On the other hand,overexpression of IRS-1 promotes estrogen-independence for growth and transformation. InER-negative breast cancer cells, usually displaying a more aggressive phenotype, the levelsof the IGF-IR and IRS-1 are often low and IGF is not mitogenic, yet the IGF-IR is stillrequired for metastatic spread. Consequently, IGF-IR function in the late stages of breastcancer remains one of the most important questions to be addressed before rationalanti-IGF-IR therapies are developed.     

妊娠期乳腺癌

目的：介绍妊娠期乳腺癌的研究进展。方法：复习近年来有关文献并进行综述。结果：妊娠期乳腺癌常被延误诊断，确诊主要靠穿刺细胞学检查和活检。治疗原则同一般乳腺癌，但需考虑胎儿因素；终止妊娠并不能改善预后。结论：妊娠期乳腺癌与普通乳腺癌相比，临床诊断更晚，预后更差，但与同年龄同期乳腺癌比较，两者的预后差异并不明显。早期乳腺癌患者治疗2年后可考虑再次妊娠。     

类固醇受体辅活化因子家族与乳腺癌

目的探讨类固醇受体辅活化因子家族在乳腺癌发生、发展、治疗、预后等方面的作用。方法对近年来有关类固醇受体辅活化因子家族成员在乳腺癌中作用研究进展的文献进行综述分析。结果类固醇受体辅活化因子是多种类固醇激素与类固醇受体结合并发挥生物学活性的必需因子，是诱导乳腺癌发生、发展和复发的重要辅助因子，同时也是判断乳腺癌预后的重要预示因子。结论抑制类固醇受体辅活化因子的表达及其相关信号通路可能是今后预防和治疗乳腺癌的一种有效途径。