MUC1在不同免疫表型乳腺癌组织中的强阳性表达及其与预后的关系

目的探讨黏蛋白1(mucin1,MUC1)强阳性表达在不同免疫表型乳腺癌中对指导预后及个体化治疗的意义。方法采用免疫组织化学法检测335例乳腺癌组织中ER、PR和HER2的表达,将乳腺癌分为四个免疫表型,采用免疫组织化学法测定各免疫表型中MUC1的阳性及强阳性表达情况,并对其与不同免疫表型乳腺癌预后的关系进行统计分析。结果 335例乳腺癌患者中MUC1强阳性表达率为46.3%,MUC1强阳性表达患者5年总生存率低于非强阳性表达者,两者之间差异存在统计学意义(P<0.05)。335例乳腺癌中ER+/PR+、HER2-型130例,ER+/PR+、HER2+型64例,ER-、PR-、HER2+型67例,ER-、PR-、HER2-型74例;MUC1强阳性表达率分别为59.2%、56.3%、32.8%和27.0%,MUC1强阳性表达与乳腺癌免疫表型相关(P<0.01)。预后分组分析表明ER+/PR+、HER2-型,ER-、PR-、HER2+型乳腺癌患者中,MUC1强阳性表达患者5年总生存率低于非强阳性表达者,差异有统计学意义(P<0.05)。结论 MUC1强阳性表达与乳腺癌免疫表型相关,在不同免疫表型乳腺癌预后中的作用也有所不同,在ER+/PR+、HER2-型及ER-、PR-、HER2+型乳腺癌中MUC1强阳性表达提示预后较差。     

雌激素孕激素受体阳性与雌激素受体阳性孕激素受体阴性乳腺癌的临床研究

目的探讨雌激素孕激素受体阳性与雌激素受体(ER)阳性孕激素受体(PR)阴性乳腺癌的临床病理特征及预后因素分析。方法收集2012年1月至2015年12月山东省肿瘤医院收治的398例女性乳腺癌患者的临床资料,分析病理学特征。应用χ2检验比较不同组的差异;应用COX回归模型分析疾病进展相关因素。结果低ER水平(HR 5.59,95%CI:2.42~12.95,P0.001)、低PR水平(HR 0.19,95%CI:0.04~0.90,P0.05)和高Ki-67增殖指数(HR 5.84,95%CI:1.91~17.85,P0.05)的患者复发率更高。ER+/PR+患者与ER+/PR-患者在肿瘤体积(P0.001)、病理分期(P0.001)、Ki-67水平(≥20%)(P0.001)、Her-2阳性表达(P0.05)等方面比较,差异有统计学意义。结论 ER+/PR-乳腺肿瘤比ER+/PR+乳腺肿瘤具有更强的侵袭性。     

乳腺癌干细胞激素受体与HER-2表达生物学意义的分析

目的:探讨雌激素受体(ER)、孕激素受体(PR)和人类表皮生长因子受体2(HER-2)在乳腺癌干细胞(BCSCs)和其分化细胞中的表达及意义。方法:选取乳腺浸润性导管癌新鲜标本30例,采用机械分离法将乳腺癌组织块制备成单细胞悬液,通过免疫磁珠两步法从中分离出BCSCs(CD44+CD24-/low细胞)和乳腺癌分化细胞(CD24+细胞和CD44-CD24-细胞),应用免疫细胞化学Envision二步法检测两组细胞ER、PR和HER-2的表达情况。结果:BCSCs ER-表达率为83.3%(25/30),分化细胞ER-表达率为53.3%(16/30),两者差异有统计学意义,P=0.025;BCSCs PR-表达率为76.7%(23/30),分化细胞PR-表达率为23.3%(7/30),两者差异有统计学意义,P=0.000;BCSCs HER-2-表达率为83.3%(25/30),分化细胞HER-2-表达率为53.3%(16/30),两者差异有统计学意义,P=0.025;BCSCs和分化细胞表型构成不同(P=0.000),BCSCs以ER-、PR-及HER-2-表型为主,占66.7%(20/30),乳腺癌分化细胞以ER和(或)PR+、HER-2-表型为主,占43.3%(13/30)。结论:BCSCs ER、PR和HER-2均可呈现阳性或阴性表达,但以阴性表达为主,随着BCSCs的分化,其阳性表达率明显升高。BCSCs的表型以ER-、PR-及HER-2-为主,这可能是部分患者内分泌治疗失败的主要原因。     

AR在不同ER状态乳腺癌中的表达及临床病理意义

  目的  探讨雄激素受体（AR）在不同雌激素受体（ER）状态乳腺癌中的表达与临床病理特征间的关系及预后。  方法  从乳腺浸润性导管癌ER阳性和阴性病例中分别随机选取111例（ER+组）与113例（ER-组）,共计224例。采用免疫组化方法检测AR、ER、PR、HER-2、Ki-67、P53表达,对不同ER状态乳腺癌中AR表达与临床病理资料及预后因素进行分析。  结果  AR在浸润性导管癌中的阳性表达率为67.9%（152/224）,ER+组和ER-组分别为80.2%（89/111）、55.8%（63/113）。ER+组中AR的表达与肿瘤大小、组织学分级、pTNM分期和有无淋巴结转移相关（P < 0.05）;在ER-组中AR的表达与组织学分级、HER-2表达、绝经状态相关（P < 0.05）。单因素生存分析显示在ER+组和ER-组AR阳性者均具有较好的预后（P < 0.001,P=0.046）,Cox多因素回归分析显示在ER+组AR表达可作为影响无瘤生存的独立因素。  结论  AR可以作为指导临床内分泌治疗新的靶标,为不同ER状态乳腺癌激素治疗提供依据。      

激素受体和HER-2及Ki-67预测乳腺癌新辅助化疗疗效价值的分析

目的:探讨乳腺癌组织中雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(HER-2)及Ki-67的表达状态对新辅助化疗反应的预测作用以及化疗前后其表达差异对疗效的影响。方法:免疫组织化学方法检测新辅助化疗前后118例乳腺癌组织的ER、PR、HER-2及Ki-67的表达情况,并分析其与新辅助化疗疗效的关系。结果:118例新辅助化疗乳腺癌病例中,ER-和PR-组pCR分别为26.1%和27.1%,明显高于ER+组11.1%和PR+组6.8%,P=0.003。HER-2和Ki-67的表达对新辅助化疗疗效无显著影响。新辅助化疗前ER、PR与Ki-67的表达呈明显负相关,P<0.001;新辅助化疗后Ki-67的高表达病例数显著减少,P=0.001。结论:ER-/PR-的患者对新辅助化疗更为敏感,Ki-67在化疗后发生了显著下调,提示新辅助化疗能降低肿瘤的增殖活性。ER、PR及Ki-67可以作为新辅助化疗疗效的预测指标。     

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。     

雌孕激素受体与女性原发乳腺癌术后复发转移关系的临床研究

目的:分析乳腺癌患者雌激素受体(es-trogen receptor,ER)和孕激素受体(progesteronereceptor,PR)状态与术后复发、转移部位的关系。方法:1989~1994年经天津医科大学附属肿瘤医院收治乳腺癌病例且雌、孕激素受体明确、术后随访完整的病例1372例。根据ER和PR状态分组,总结ER和PR状态与首次治疗后发生复发、转移部位的关系。结果:ER /PR 组患者皮肤、骨骼转移率为10·91%,明显高于ER-/PR-组(5·56%),P=0·0053;ER-/PR-组内脏转移率为15·56%,高于ER /PR 组(3·64%),P=0·0000。激素依赖性组5年总生存率和无瘤生存率(82·31%,80·04%)高于非激素依赖性组(77·22%,73·89%),P<0·05。两组10年总生存率、无瘤生存率并无区别。结论:乳腺癌在晚期转移部位与ER、PR受体状态有关,ER /PR 组5年总生存率、无瘤生存率高于ER-/PR-组,进行综合治疗是提高总生存率、无瘤生存率的关键。     

乳腺癌干细胞临床与基础研究的进展

乳腺癌是一类高度异质性的肿瘤,包括18种组织病理学类型和5 种分子亚型。乳腺癌干细胞（CSCs）是乳腺癌组织中极少数具有自我更新能力和多向分化潜能的细胞,具有肿瘤启动作用。CD44+/CD24-/low表型为乳腺CSCs的标志,大约30% 乳腺癌组织中存在CD44+/CD 24-/low表型细胞,CD44+/CD 24-/low表型细胞与病理组织学类型有关,在呈现CD44+/CD 24-/low表型的肿瘤中,浸润性导管癌所占比例最多（78%）,其次为髓样癌（11%）和浸润性小叶癌（7%）。 CD44+/CD 24-/low表型细胞与乳腺癌的分子亚型有关,在依据基因表达谱得到的5 种分子亚型中,CD44+/CD 24-/low表型在基底样癌中最常见。乳腺癌干细胞通常为ER- 和PR- 的表型,但ER- 和PR- 的多潜能干细胞能产生ER+ ,PR+ 的肿瘤细胞。HER2 过表达能够增加CSCs的数量并促进乳腺癌的发生、进展和浸润,但乳腺癌组织中CD44+/CD 24-/low表型通常与HER2 低表达或阴性表达呈正相关。迄今有关干细胞与乳腺癌的临床基础研究提出了更多新的问题,引发了更多的思考。      

血清睾酮水平与乳腺癌雌、孕激素受体表达的相关性研究

目的:回顾性研究血清睾酮（testosterone,T）水平与乳腺癌雌激素受体（estrogen receptor,ER）,孕激素受体（progesterone receptor,PR）表达的相关性。方法:回顾性分析2016年1月至2018年12月在南京市妇幼保健院进行体检和治疗的63例健康女性,99例良性肿瘤,204例乳腺癌的临床病理资料,比较三组之间的血清睾酮水平的差异。将所有204例乳腺癌患者根据睾酮水平由低到高排序,按四分位数分为4组,采用Logistic回归比较不同睾酮水平下4组乳腺癌患者ER、PR、Her2表达状态的比值比（OR）。结果:乳腺癌组血清睾酮水平与乳腺良性肿瘤组、健康对照组相比差异均无统计学意义（P＞0.05）。ER+和PR+乳腺癌患者中血清睾酮水平分别高于ER-和PR-患者,而Her2+乳腺癌患者中血清睾酮水平低于Her2-患者,差异均有统计学意义（P＜0.05）。采用Logistic回归计算OR值,根据绝经与否进一步分层,其中T≥0.44 ng/mL组相对于T≤0.22 ng/mL组ER阳性表达的总体OR值为2.46（95%CI=1.04~5.86,P=0.042）,绝经前OR值为3.77（95%CI=1.11~12.80,P=0.034）,绝经后OR值为1.05（95%CI=0.28~3.92,P=0.945）;T≥0.44 ng/mL组相对于T≤0.22 ng/mL组PR阳性表达的总体OR值为3.69（95%CI=1.60~8.49,P=0.002）,绝经前OR值为4.80（95%CI=1.51~15.23,P=0.008）,绝经后OR值为1.78（95%CI=0.47~6.71,P=0.396）,结果显示绝经前乳腺癌患者中ER、PR的阳性表达与血清睾酮水平呈现出明显的正相关性;而Her2阳性表达与血清睾酮水平在总体、绝经前、绝经后乳腺癌患者中均未表现出明显的负相关性。结论:高血清睾酮水平与乳腺癌ER、PR的阳性表达呈正相关,在绝经前乳腺癌患者中表现尤为显著。血清睾酮水平可以作为预测绝经前激素受体状态的标志物之一。     

激素受体和人表皮生长因子受体2的表达与改良根治术后淋巴结阳性乳腺癌患者预后的关系

目的 探讨雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)的表达情况与行改良根治术后腋窝淋巴结阳性乳腺癌患者预后的关系.方法 收集835例行改良根治术后腋窝淋巴结阳性乳腺癌患者的临床和随访资料.根据ER、PR和Her-2的免疫组化检查结果,将患者分为Rec-/Her-2-(三阴性)组、Rec-/Her-2+组、Rec+/Her-2+组和Rec+/Her-2-组,比较其局部区域复发率、远处转移率、无瘤生存率和总生存率.结果 835例患者中,三阴性组141例,Rec-/Her-2+组99例,Rec+/Her-2+组157例,Rec+/Her-2-组438例.Rec+/Her-2-患者的5年局部区域复发率为6.2%,低于其他患者(12.9%,P=0.004).与受体阳性组(Rec+/Her-2+和Rec+/Her-2-)比较,受体阴性组(Rec-/Her-2-和Rec-/Her-2+)有较高的5年远处转移率(26.4%和19.7%,P=0.0008)、较低的5年无瘤生存率(66.7%和75.6%,P=0.0001)和较低的5年总生存率(71.4%和84.2%.P=0.0000).多因素Cox回归分析结果显示,激素受体和Her-2的表达状态是乳腺癌患者局部区域复发、远处转移、无瘤生存和总生存的独立影响因素(均P<0.05),Rec+/Her-2-患者的局部区域复发风险低,受体阴性患者发生远处转移和死亡的风险高.结论 ER、PR和Her-2是改良根治术后腋窝淋巴结阳性乳腺癌患者的独立预后因素.     

Survival Benefit of Tamoxifen in Estrogen Receptor-Negative and Progesterone Receptor-Positive Low Grade Breast Cancer Patients

Purpose

This study aimed to analyze the efficacy and prognostic significance of adjuvant tamoxifen in breast cancer patients with various hormone receptor statuses.

Methods

Typically, 1,260 female breast cancer patients were recruited in this study. The correlation between estrogen receptor (ER)/progesterone receptor (PR) phenotypes and clinical characteristics was investigated, and the survival rate was assessed after 5-year follow-up.

Results

The 5-year overall survival (85%) was better in women under the age of 50 years. Patients with ER+/PR+ tumors had a better 5-year survival rate (94%); those with ER-/PR- tumors experienced the worst outcome (74% survival rate); whereas single-positive cases were in between. In 97 out of 128 patients with ER-/PR+ tumors, tamoxifen was given as adjuvant hormonal therapy, and it increased the survival benefit in the lower grade group in terms of overall survival and disease-free survival (p=0.01 and p=0.03, respectively).

Conclusion

For high-grade tumors with ER-/PR+, adjuvant tamoxifen therapy may have no survival benefit, whereas for the patients with low-grade ER-/PR+ tumors, adjuvant tamoxifen therapy is highly suggestive.     

Characterizing Clinicopathologic Features of Estrogen Receptor-Positive/Progesterone Receptor-Negative Breast Cancers

BackgroundWhile most estrogen receptor-positive (ER+) breast cancers express progesterone receptor (PR), a small subset of tumors exhibits an ER+/PR- phenotype despite the fact that PR is an ER-dependent gene product. Previous studies have shown that these tumors are generally associated with a worse clinical outcome when compared to the ER+/PR+ breast cancers, indicating that they are clinically and probably genetically different entities.MethodsWe characterized the clinicopathologic features of ER+/PR- tumors from the Surveillance, Epidemiology and End Results (SEER) database and the authors’ institutional cohort.ResultsER+/PR- tumors, constituting 12% of all breast cancers in both cohorts, less frequently occurred in Caucasians, were more likely to be of a higher histologic grade and presented with a higher stage when compared to ER+/PR+ tumors. Conversely, ER+/PR- neoplasms were more frequently seen in Caucasians, less likely to be of a higher histologic grade and less frequently presented with an advanced clinical stage when compared to ER-/PR- tumors. Further, the ER+/PR- tumors were associated with a disease-specific survival intermediate to that between ER+/PR+ and ER-/PR- tumors. An ER H-score of ≥270 was associated with a significantly superior relapse-free survival in the ER+/PR- tumors, suggesting that a near-maximal ER expression is needed to compensate for the altered ER signaling in these tumors. Pathologic stage and HER2 status were independent prognostic factors in the ER+/PR- tumors. These findings may provide additional insights in directing clinical decision making for individualized systemic therapy in the pursuit of precision medicine.     

Association of Poor Prognosis Subtypes of Breast Cancer with Estrogen Receptor Alpha Methylation in Iranian Women

Breast cancer is a prevalent heterogeneous malignant disease. Gene expression profiling by DNA microarraycan classify breast tumors into five different molecular subtypes: luminal A, luminal B, HER-2, basal and normallikewhich have differing prognosis. Recently it has been shown that immunohistochemistry (IHC) markersincluding estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2(Her2), can divide tumors to main subtypes: luminal A (ER+; PR+/-; HER-2-), luminal B (ER+;PR+/-; HER-2+),basal-like (ER-;PR-;HER2-) and Her2+ (ER-; PR-; HER-2+). Some subtypes such as basal-like subtype have beencharacterized by poor prognosis and reduced overall survival. Due to the importance of the ER signaling pathwayin mammary cell proliferation; it appears that epigenetic changes in the ERα gene as a central component of thispathway, may contribute to prognostic prediction. Thus this study aimed to clarify the correlation of differentIHC-based subtypes of breast tumors with ERα methylation in Iranian breast cancer patients. For this purposeone hundred fresh breast tumors obtained by surgical resection underwent DNA extraction for assessedment oftheir ER methylation status by methylation specific PCR (MSP). These tumors were classified into main subtypesaccording to IHC markers and data were collected on pathological features of the patients. ERα methylation wasfound in 25 of 28 (89.3%) basal tumors, 21 of 24 (87.5%) Her2+ tumors, 18 of 34 (52.9%) luminal A tumors and7 of 14 (50%) luminal B tumors. A strong correlation was found between ERα methylation and poor prognosistumor subtypes (basal and Her2+) in patients (P<0.001). Our findings show that ERα methylation is correlatedwith poor prognosis subtypes of breast tumors in Iranian patients and may play an important role in pathogenesisof the more aggressive breast tumors.     

The estrogen receptor negative-progesterone receptor positive breast carcinoma is a biological entity and not a technical artifact

The ER-/PR+ breast tumor may be the result of a false ER negative result. The aim of this study was to investigate whether there is a difference in patient and tumor characteristics of the ER-/PR+ phenotype in an Asian setting. A total of 2629 breast cancer patients were categorized on the basis of their age, ethnicity, tumor hormonal receptor phenotype, grade and histological type. There were 1230 (46.8%) ER+/PR+, 306 (11.6%) ER+/PR-, 122 (4.6%) ER-/PR+ and 972 (37%) ER-/PR-. ER-/PR+ tumors were 2.5 times more likely to be younger than 50 years at diagnosis (OR: 2.52; 95% CI: 1.72-3.67). Compared to ER+/PR+ tumors, the ER-/ PR+ phenotype was twice more likely to be associated with grade 3 tumors (OR:2.02; 95%CI: 1.00-4.10). In contrast, compared to ER-/PR- tumors, the ER-/PR+ phenotype was 90% less likely to be associated with a grade 3 tumor (OR: 0.12; 95%CI:0.05-0.26), and more likely to have invasive lobular than invasive ductal histology (OR: 3.66; 95%CI: 1.47-9.11). These results show that the ER-/PR+ phenotype occurs in a younger age group and is associated with intermediate histopathological characteristics compared to ER+/PR+ and ER-/PR- tumors. This may imply that it is a distinct entity and not a technical artifact.     

Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype

Introduction

Estrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression.

Methods

We integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses’ Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival.

Results

In a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets.

Conclusion

ER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.     

Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the surveillance, epidemiology, and end results database.

PURPOSE: Hormone receptor expression (presence-positive or absence-negative) may reflect different stages of one disease or different breast cancer types. Determining whether hormone receptor expression represents one or more breast cancer phenotypes would have important paradigmatic and practical implications. METHODS: Breast cancer records were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. The study included 19,541 non-Hispanic white women with node-negative breast cancer. Standard tumor cell characteristics and breast cancer-specific survival were analyzed by independent estrogen receptor (ER+ and ER-), independent progesterone receptor (PR+ and PR-), and joint ERPR expression (ER+PR+, ER+PR-, ER-PR+, and ER-PR-). RESULTS: Age frequency density plots by hormone receptor expression showed two overlapping breast cancer populations with early-onset and/or late-onset etiologies. Independent ER+ and PR+ phenotype were associated with smaller tumor sizes, better grade, and better cancer-specific survival than ER- and PR- breast cancer types. Joint ERPR phenotype exhibited biologic gradients for tumor size, grade, and cancer-specific survival, which ranked from good to worse for ER+PR+ to ER+PR- to ER-PR+ to ER-PR-. CONCLUSION: Variations of standard tumor cell characteristics and breast cancer-specific survival by hormone receptor expression in white patients with node-negative breast cancer suggested two breast cancer phenotypes with overlapping etiologies and distinct clinical features.     

Alcohol intake and risk of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis of epidemiological studies

The association between alcohol consumption and an increased risk of breast cancer has been established. It is still unclear however, whether this relationship differs across the estrogen receptor (ER) and progesterone receptor (PR) tumors subtypes. To provide a quantitative assessment of the association between alcohol intake and the risk of ER-/PR-defined breast cancer, we conducted a meta-analysis of cohort and case-control studies. Studies were identified by a literature search of PubMed through April 20, 2007 and by searching the reference lists of relevant articles. Summarized risk estimates (REs) with 95% confidence intervals (CIs) were calculated using random-effects models. The summarized results of the meta-analysis comparing the highest versus the lowest consumption categories showed statistically significant higher risks of developing all ER+ (27%), all ER- (14%), ER+PR+ (22%) and ER+PR- (28%), but not ER-PR- tumors. The dose-response meta-analysis showed that an increase in alcohol consumption of 10 g of ethanol per day was associated with statistically significant increased risks for all ER+ (12%), all ER- (7%), ER+PR+ (11%) and ER+PR- (15%), but not ER-PR-. A statistically significant heterogeneity of the REs across all ER+ versus ER-PR- was observed (p(heterogeneity) = 0.02). The summarized results from studies with adjustment for postmenopausal hormone use, body mass index and family history of breast cancer were higher and statistically significantly different from those without. The observed positive associations with alcohol for ER+PR+ and ER+PR- tumors cannot be explained by estrogen-dependent pathway only. Further studies need to clarify the biological mechanisms.