乳腺癌组织中p53、nm23-H1基因表达及其与绝经状态、淋巴结转移的相关性

[目的]研究乳腺癌患者中p53和nm23-H1基因表达,及其与绝经状态及腋窝淋巴结转移的关系.[方法]采用免疫组织化学SP方法检测60例乳腺癌组织中p53和nm23-H1的表达.[结果]60例乳腺癌患者中,p53和nm23-H1的阳性表达率分别为73.3%(44/60)和66.7%(40/60);在绝经前患者中p53和nm23-H1的阳性表达率分别为66.7%(16/24)和50.0%(12/24),而在绝经后患者中两者的阳性表达率分别为77.8%(28/36)和77.8%(28/36).在绝经后患者中p53和nm23-H1基因的阳性表达与腋窝淋巴转移呈显著性相关(P=0.019和P=0.019).[结论]p53可能参与绝经前妇女乳腺癌的发生,可能促进绝经后乳腺癌的转移;而nm23-H1可能参与绝经后乳腺癌的转移.     

癌症分子基础与临床(各论) 第十四讲 乳腺和卵巢肿瘤的分子基础与临床

一、家族性癌及诱发乳腺癌和卵巢癌的遗传性综合征乳腺癌和卵巢癌都有一定的家族史，流行病学调查发现大约5％一10％的乳腺癌是家族性的。如有一个嫡亲患乳腺癌，则发生乳腺癌的危险性增加1．5——3倍。如有两个近亲患乳腺癌，则增加7倍。发病的年龄越小，在亲属中患乳腺癌的危险越大。如在30岁前发生乳腺癌，则她的母亲和姐妹在ho岁前患乳腺癌的危险估计为0．16；如在3O岁一39岁，则为0．10；40岁一hen岁，为0．贿；50岁一54岁，为0．阳；对照一般人群中的危险为0．03。患双侧性乳腺癌的病人的亲属的危险比患单侧性者高5倍。这些流行病学…     

绝经前和绝经后乳腺癌患者中ER、nm23-H1、c-erbB-2基因的表达及其关系

目的探讨ER、nm23-H1和c-erbB-2基因在绝经前（premenopausal）和绝经后（postmenopausal）乳腺癌患者中的表达,以及三者之间的关系。方法本研究采用免疫组化S-P方法检测60例乳腺癌组织中ER、nm23-H1和c-erbB-2的表达。结果在绝经前乳腺癌患者中ER、nm23-H1及c-erbB-2的阳性表达率为45.8%、50.0%和50.0%,而在绝经后患者中三者的阳性表达率为55.6%、77.8%和58.3%。在绝经后患者中乳腺癌组织中nm23-H1的表达随着ER表达的增加而增加,两者在统计学上有明显的相关性（P=0.033）,而在绝经前患者中两者无关（P=0.229）。在绝经后患者中显示nm23-H1基因的表达与转移呈明显相关（P=0.019）,但在绝经前患者中该基因表达与转移无关（P=0.680）。在绝经后患者中ER呈阴性的乳腺癌组织的c-erbB-2表达明显增加,且两者的表达在统计学上存在明显相关性（P=0.028）,然而在绝经前患者中ER与c-erbB-2表达之间并无相关性（P=0.688）。在绝经前和绝经后患者中ER、c-erbB-2的表达与腋窝淋巴结转移均没有相关性（分别为P=0.351、P=0.425和P=0.680、P=0.704）。nm23-H1和c-erbB-2两者无论在绝经前还是绝经后患者中都没有呈现统计学上的相关性（P=0.110和P=0.593）。另外,在绝经前和绝经后患者中ER、c-erbB-2与组织学类型、分化程度、患者年龄及病变部位均没有相关性（P〉0.05）。结论ER可能只在绝经后而不是在绝经前的乳腺癌患者中才明显地表现出对c-erbB-2表达的抑制作用和对nm23-H1表达的促进作用。     

乳腺癌的危险因素与绝经状态的关系

有些作者认为乳腺癌的危险或保护因素在诊断年龄不同的乳腺癌患者之间有差异。已有的研究表明卵巢活动对乳腺癌的发生具有重要作用。诊断于绝经前(卵巢有活动)与绝经后(卵巢无活动)的乳腺癌的危险因素是否不同呢?本文的目的旨在通过对绝经前、绝经后诊断的乳腺癌患者及相应对照的某些特征进行分析,探索上海地区乳腺癌的危险因素与绝经状态的关系,为乳腺癌的发病机理和可行的预防措施提供线索。     

诺雷德联合瑞宁得治疗绝经前和围绝经期晚期乳腺癌临床疗效观察

目的：观察诺雷德联合瑞宁得治疗绝经前和围绝经期晚期ER（＋）和（或）PR（＋）乳腺癌的内分泌治疗疗效和不良反应。方法：36例绝经前和围绝经期晚期乳腺癌患者,皮下注射诺雷德3．6mg,每28日1次,激素水平达绝经期后同时服用瑞宁得,每日1次,每次ling。结果：完全缓解（CR）1例,部分缓解（PR）10例,稳定（SD）15例,进展（PD）10例,总有效率30．6％,临床获益率为58．3％。ER和PR同时阳性表达的及组织学分级I级的有效率高,P〈0．05;与HER-2表达无关,P〉0．05;胸壁局部复发和骨转移治疗疗效优于内脏等其他转移,P〈0．05。激素达绝经水平的诺雷德应用中位次数为3次。不良反应包括潮热、多汗、关节痛、乏力等,可耐受。结论：诺雷德联合瑞宁得治疗疗效肯定,不良反应轻微,是绝经前和围绝经期晚期乳腺癌内分泌治疗较好的选择。     

肥胖、糖尿病和高血压与子宫内膜癌前病变和癌的相关性分析

[目的]分析绝经前妇女子宫内膜发生恶变的相关危险因素。[方法]回顾性分析630例因阴道出血就诊并经病理证实绝经前子宫内膜病变患者的临床资料,比较分析良性病变组（595例）和恶性病变组（35例）患者的临床特征以及子宫内膜恶变的相关危险因素。恶性病变相关高危因素分析采用Logistic多元回归分析。[结果]调整年龄、子宫内膜厚度因素后,肥胖（RK=2．938,95％CI：1．060～8．142）、糖尿病（RR=9．945,95％CI：3．297—29．997）患子宫内膜癌前病变,癌恶性病变的风险增加。且有统计学差异：高血压患子宫内膜癌前病变／癌恶性病变的风险是无高血压患者的1．752倍（95％CI：0．903～7．831）,无统计学差异。[结论]肥胖、糖尿病与子宫内膜癌密切相关。因此,若能尽早改变生活方式,如合理饮食、增加活动量则有可能在很大程度上预防子宫内膜癌的发生。     

绝经前后妇女血清IGF-1水平与乳腺癌发病危险度的Meta分析

目的:探讨绝经前后妇女血清胰岛素样生长因子-1(IGF-1)水平增高与乳腺癌发病的相关程度.方法:通过PubMed、Medline、CNKI、和维普检索1993-2007年已发表的IGF-1和乳腺癌关系的病例对照研究或队列研究文献资料,剔除不符合要求的文献,分类后应用Stata9.0软件进行一致性检验和数据合并.结果:6篇病例对照研究及5篇队列研究,共11篇文献入选;与对照组相比,未绝经妇女IGF-1的高水平与乳腺癌的发生有明显相关性,P<0.01,合并OR值为1.57,95%CI(1.26～1.95);而在绝经后妇女中,高水平的IGF-1与乳腺癌发生没有明显相关性,P=0.384,合并OR值为1.11,95%CI(0.88～1.39).结论:对绝经前的人群检测血清IGF-1水平有助于筛选和确定乳腺癌高危患者,有利于早期诊断及判断预后.     

Luminal A型乳腺癌的激素受体表达与绝经的相关性

目的探讨Luminal A型乳腺癌的激素受体表达水平与绝经的相关性,进一步认识该类乳腺癌的生物学特性。方法回顾性分析江苏省肿瘤医院2009年1月至2012年10月收治的135例LuminalA型乳腺癌患者的雌激素受体（estrogenreceptor,ER）及孕激素受体（progesteronereceptor,PR）的表达水平（高表达（H）〉50％;低表达（L）≤50％）,比较ER、PR的不同表达分组在绝经前后患者中的差异及ER、PR间的相关性。结果绝经前LuminalA型乳腺癌ER—H／PR-H表达最常见（63．8％）;ERH／PR—L表达在绝经后患者中最常见（51．1％）,在绝经前少见（17．0％）。ER、PR的相关性在绝经前比绝经后更明显（P值：0．003VS．0．047）。结论绝经前后的LuminalA型乳腺癌患者存在ER、PR的不同表达的差异性分布,体内雌激素水平可能是引起差异的原因。     

绝经与子宫内膜癌预后的关系

目的探讨绝经前后妇女子宫内膜癌的临床病理特征以及绝经能否作为子宫内膜癌的预后因素。方法将212例子宫内膜癌患者按是否绝经分为2组：未绝经组78例，绝经组134例。分析两组患者的临床病理特征及预后。结果未绝经组与绝经组相比，不孕患者比例低（分别为14．1％和19．2％）。高血压患者比例低（分别为4．5％和33．6％），组织分级低（G3分别为12．3％和26．2％）、深肌层浸润少见（分别为9．0％和29．1％），复发少（分别为5．1％和12．7％），生存率高。上述各项均有显著性差异（P〈0．05）。结论未绝经子宫内膜癌者的预后较好，与临床病理特点有关。绝经可以作为子宫内膜癌的1个独立的预后因素。     

绝经妇女卵巢肿瘤诊治分析

卵巢肿瘤是妇女常见病 ,恶变率高。卵巢癌由于不易早期诊断 ,是生殖道肿瘤中死亡率最高的一种[1] ,值得关注。绝经妇女内分泌的特殊性决定了卵巢肿瘤的发展趋向有别于中青年妇女。我院 1996年 5月～2 0 0 0年 12月共收治绝经妇女卵巢肿瘤 78例 ,现对其诊断、治疗、愈后分析如下。1　资料与方法1 1　研究对象　回顾总结我院 1996年 5月～ 2 0 0 0年12月间诊治的绝经妇女患卵巢肿瘤者共 78例 ,年龄5 1～ 78岁 ,平均 6 3 8岁。1 2　方法　患者入院后给予必要生化及物理检查 ,控制内、外科疾患后行手术治疗 ,术中及术后病变组织行细胞学检查。1 …     

Association of Family History and Other risk factors with Breast Cancer Risk among Japanese Premenopausal and Postmenopausal Women

Objectives: To determine the impact of family history (FH) on anthropometric and reproductive risk factors for breast cancer, a case-referent study was conducted using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Methods: In total, 1584 breast cancer cases were included and 15,331 women, confirmed as free of cancer, were recruited as the referents. Odds ratios and 95% confidence intervals were determined by logistic regression analysis. Separate analyses were performed for premenopausal and postmenopausal women. Results: Height, weight, and current body mass index (BMI) were positively associated with postmenopausal breast cancer regardless of FH, while these anthropometric factors did not alter risk in premenopausal women. The impacts of height and weight on postmenopausal breast cancer were more pronounced among FH women. There was little association with reproductive risk factors for premenopausal or postmenopausal breast cancer in FH cases, in clear contrast to the non-FH cases. Conclusions: These findings suggest some differences in risk impact of common etiologic factors between familial breast cancer and sporadic cases that may give pointers to further analysis of host-specific factors. They imply that avoidance of obesity after menopause may reduce the risk of breast cancer, regardless of FH.     

四川省女性ERα基因多态性与乳腺癌风险关系的病例对照研究

目的：探讨雌激素受体XbaⅠ、PvuⅡ基因多态性与四川汉族女性乳腺癌患病风险的关系。方法：采用病例对照研究设计,序贯收集乳腺癌病例221例,健康对照252例。采用问卷调查收集一般人口学特征、身高、体重、生殖生育史、雌激素药物服用史等信息;采用限制性片段长度多态性技术,检测ERα基因XbaⅠ（ rs9340799） A/G（x/X）、PvuⅡ（rs2234693）C/T（P/p）基因突变情况。采用非条件多因素Logistic回归模型分析XbaⅠ、PvuⅡ基因多态性的独立效应及联合效应。按绝经状态进行亚组分析。结果：在总人群及不同绝经状态亚组中,XbaⅠ、PvuⅡ基因型分布与乳腺癌患病风险无统计学关联（ P〉0．05）。以xxPP野生基因型组合做参照,在总人群中,只携带X等位基因能明显降低乳腺癌患病风险（OR=0．31,95%CI：0．11～0．90）,该效应与X、p等位基因联合暴露效应接近（OR=0．39,95%CI：0．15～1．00）。在绝经前女性中,上述暴露组合效应分别为0．12（0．03～0．54）和0．25（0．07～0．89）。结论：雌激素受体 XbaⅠX等位基因可能对乳腺癌患病风险具有保护效应。     

Impact of established risk factors for breast cancer in nulligravid Japanese women

BACKGROUND: The mechanism by which pregnancy impacts breast cancer risk remains poorly understood. There is a need for detailed quantification of risk in nulliparous women. We therefore have undertaken a case-referent study of breast cancer employing data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan, examining the impact of reproductive and anthropometric factors on breast cancer risk among nulligravid women compared with their parous counterparts. METHODS: In total, 2032 breast cancer cases were included, and 17848 women, confirmed as free of cancer, were recruited as a reference group. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by multiple logistic regression analysis. RESULTS: A protective effect of later age at menarche was observed among parous women, but it did not alter risk in nulligravid cases. The risk increment with a family history appeared to be most pronounced among premenopausal cases with no history of pregnancy (OR=2.68, 95% CI: 1.41-5.11). Among postmenopausal women, positive associations with height and current body mass index (BMI) in the nulligravid group were similar to those observed in the parous group. The present study indicated that age at menopause, family history in premenopausal women, and height and obesity in postmenopausal women seemed to exert more influence in nulligravid women. Formal tests for interaction between maternity status and these factors, however, did not prove statistically significant. CONCLUSION: Our findings suggest that established risk factors for breast cancer have an additive impact with nulligravid status. Thus, it is implied that obesity control for all women, including nulliparous individuals, is important from a practical viewpoint for primary breast cancer prevention.     

Dietary factors protective against breast cancer in Japanese premenopausal and postmenopausal women

Since components of the Japanese diet that might be responsible for the relatively low breast cancer incidence rates observed in Japan have not been clarified in detail, a case-referent study with reference to menopausal status was conducted using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). In total, 2,385 breast cancer cases were included, and 19,013 women, confirmed as free of cancer, were recruited as the reference group. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined by multiple logistic regression analysis. There were reductions in risk associated with high intake of milk and green-yellow vegetables (green leafy vegetables, carrots and pumpkins) among both pre- and postmenopausal women. The protective effects of the Japanese diet were more prominent among postmenopausal than premenopausal women. The adjusted OR of fish consumption (5 or more times per week vs. fewer than 3 times per month) was 0.75 (95% CI 0.57-0.98, p(trend) = 0.01) for postmenopausal breast cancer. A significant decrease in postmenopausal breast cancer risk was also observed for increasing intake of fruit (OR = 0.61, 95% CI 0.41-0.91). Thus, traditional Japanese dietary factors may protect against breast cancer development, especially among postmenopausal women.     

Body size, mammographic density, and breast cancer risk.

BACKGROUND: Greater weight and body mass index (BMI) are negatively correlated with mammographic density, a strong risk factor for breast cancer, and are associated with an increased risk of breast cancer in postmenopausal women, but with a reduced risk in premenopausal women. We have examined the associations of body size and mammographic density on breast cancer risk. METHOD: We examined the associations of body size and the percentage of mammographic density at baseline with subsequent risk of breast cancer among 1,114 matched case-control pairs identified from three screening programs. The effect of each factor on risk of breast cancer was examined before and after adjustment for the other, using logistic regression. RESULTS: In all subjects, before adjustment for mammographic density, breast cancer risk in the highest quintile of BMI, compared with the lowest, was 1.04 [95% confidence interval (CI), 0.8-1.4]. BMI was associated positively with breast cancer risk in postmenopausal women, and negatively in premenopausal women. After adjustment for density, the risk associated with BMI in all subjects increased to 1.60 (95% CI, 1.2-2.2), and was positive in both menopausal groups. Adjustment for BMI increased breast cancer risk in women with 75% or greater density, compared with 0%, increased from 4.25 (95% CI, 1.6-11.1) to 5.86 (95% CI, 2.2-15.6). CONCLUSION: BMI and mammographic density are independent risk factors for breast cancer, and likely to operate through different pathways. The strong negative correlated between them will lead to underestimation of the effects on risk of either pathway if confounding is not controlled.     

Risk Factor Analysis for Breast Cancer in Premenopausal and Postmenopausal Women of Punjab,India

Objective: Amritsar, the second largest town of agrarian state of Punjab, India reports high number of breast cancer cases every year. The present study investigated the etiology of breast cancer using various obesity indices and other epidemiological factors among breast cancer patients residing in and around Amritsar city. Methods: In this case control study, risk factors for breast cancer were analyzed in 542 female subjects: 271 females with breast cancer patients and 271 unrelated healthy females matched for age as control females. Results: Bivariate analysis for risk factors in cases and controls showed a lower risk (OR=0.65, 95% CI 0.43-0.99, p=0.04) in obese cases with BMI≥25kg/m2 as compared to subjects with normal BMI. Risk factor analysis showed that parameter which provided risk for cancer in postmenopausal women was obesity and in premenopausal women was parity. Postmenopausal women with BMI (overweight: OR=0.39, 95% CI 0.17-0.92, p=0.03; obese: OR= 0.26, 95% CI 0.13-0.52, p=0.00), WC (OR=0.17, 95% CI 0.05-0.52, p=0.00) and WHtR (p=0.02) had highr risk. Premenopausal women with 3 or less than 3 children had a higher risk (OR=5.54, 95 % CI 2.75-11.19, p=0.00) than postmenopausal women when compared to women with more than 3 children. Binary logistic regression analysis revealed that low parity (≤3) substantially increased the risk for breast cancer (OR=4.80, 95% CI 2.34-9.85, p=0.00) in premenopausal women. Conclusion: Obesity, parity associated breast cancer risk and reduced breastfeeding cumulatively predispose the premenopausal women of this region to higher risk of breast cancer.     

Genetic and environmental predictors, endogenous hormones and growth factors, and risk of estrogen receptor-positive breast cancer in Japanese women

The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. We have recently shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive subtype. It is necessary to establish risk factors capable of predicting the risk of ER-positive breast cancer that will enable the efficient selection of candidates for preventive therapy. We analyzed genetic factors, including 14 single nucleotide polymorphisms (SNPs), environmental risk factors (body mass index, age at menarche, pregnancy, age at first birth, breastfeeding, family history of breast cancer, age at menopause, use of hormone replacement therapy, alcohol intake, and smoking), serum hormones and growth factors (estradiol, testosterone, prolactin, insulin-like growth factor 1 [IGF1] and IGF binding protein 3 [IGFBP3]), and mammographic density in 913 women with breast cancer and 278 disease-free controls. To identify important risk factors, risk prediction models for ER-positive breast cancer in both pre- and postmenopausal women were created by logistic regression analysis. In premenopausal women, one SNP (CYP19A1-rs10046), age, pregnancy, breastfeeding, alcohol intake, serum levels of prolactin, testosterone, and IGFBP3 were considered to be risk predictors. In postmenopausal women, one SNP (TP53-rs1042522), age, body mass index, age at menopause, serum levels of testosterone, and IGF1 were identified as risk predictors. Risk factors may differ between women of different menopausal status, and inclusion of common genetic variants and serum hormone measurements as well as environmental factors might improve risk assessment models. Further validation studies will clarify appropriate risk groups for preventive therapy.     

Glutathione S-transferase M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer.

This study was undertaken to examine if glutathione S-transferase (GST) M1, M3, P1, and T1 genotypes affected breast cancer risk in Finnish women. The study population consisted of 483 incident breast cancer cases and 482 healthy population controls. Genotyping analyses were performed by PCR-based methods, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for known or suspected risk factors for breast cancer. When the genes were studied separately, the only significant finding was between GSTM1 null genotype and postmenopausal breast cancer risk (OR, 1.49; 95% CI, 1.03-2.15). Conversely, when the potential combined effects of the at-risk genotypes were examined, significant associations were observed only among premenopausal women. Although only a moderate risk of breast cancer was seen for premenopausal women concurrently carrying the GSTM3*B allele containing genotypes and the GSTP1 Ile/ Ile genotype (OR, 2.07; 95% CI, 1.02-4.18), the risk rose steeply if they simultaneously lacked the GSTT1 gene (OR, 9.93, 95% CI, 1.10-90.0). A borderline significant increase in the risk of breast cancer was also seen for premenopausal women with the combination of GSTM1 null, GSTP1 Ile/Ile, and GSTT1 null genotypes (OR, 3.96; 95% CI, 0.99-15.8). Our findings support the view that GST genotypes contribute to the individual breast cancer risk, especially in certain combinations.     

Body mass index and the risk for developing invasive breast cancer among high-risk women in NSABP P-1 and STAR breast cancer prevention trials

High body mass index (BMI) has been associated with an increased risk for breast cancer among postmenopausal women. However, the relationship between BMI and breast cancer risk in premenopausal women has remained unclear. Data from two large prevention trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) were used to explore the relationship between baseline BMI and breast cancer risk. The analyses included 12,243 participants with 253 invasive breast cancer events from the Breast Cancer Prevention Trial (P-1) and 19,488 participants with 557 events from the Study of Tamoxifen and Raloxifene (STAR). Both studies enrolled high-risk women (Gail score ≥ 1.66) with no breast cancer history. Women in P-1 were pre- and postmenopausal, whereas women in STAR (P-2) were all postmenopausal at entry. Using Cox proportional hazards regression, we found slight but nonsignificant increased risks of invasive breast cancer among overweight and obese postmenopausal participants in STAR and P-1. Among premenopausal participants, an increased risk of invasive breast cancer was significantly associated with higher BMI (P = 0.01). Compared with BMI less than 25, adjusted HRs for premenopausal women were 1.59 for BMI 25 to 29.9 and 1.70 for BMI 30 or more. Our investigation among annually screened, high-risk participants in randomized, breast cancer chemoprevention trials showed that higher levels of BMI were significantly associated with increased breast cancer risk in premenopausal women older than 35 years, but not postmenopausal women.     

绝经后早期乳腺癌患者术后一年内发生骨密度减低的相关因素分析

目的 探讨影响绝经后早期乳腺癌患者术后一年内发生骨密度减低的相关因素。方法 对242 例绝经后早期乳腺癌患者临床资料进行回顾性分析,并对骨密度减低的相关因素进行单因素及多因素Logistic回归分析。结果 对影响骨密度减少的10项指标进行单因素分析,显示年龄、BMI、绝经年限、AI内分泌治疗、雌二醇水平与骨密度减低显著相关（P＜0.05）;多因素Logistic回归分析显示绝经年限长、AI内分泌治疗、雌二醇低水平是骨密度减低的主要影响因素（P＜0.05）。结论 绝经后乳腺癌患者骨密度减低的主要影响因素是绝经年限长、AI内分泌治疗、雌二醇低水平,对于合并这些危险因素的乳腺癌患者,在临床工作中要足够重视并进行预防性和针对性治疗。