雌激素受体亚型在人乳腺癌的表达及意义

目的　研究人乳腺癌组织以及癌旁正常乳腺组织中雌激素受体 (ER)亚型ERα和ERβ的表达 ,及其在乳腺癌发生发展中的作用。方法　应用逆转录聚合酶链反应方法检测 30例患者乳腺癌组织以及相应癌旁正常组织中ERα和ERβ的mRNA的表达情况。结果　ERα在人乳腺癌组织的表达明显高于癌旁正常组织 (t=7 399,P <0 0 1) ,ERβ在人乳腺癌组织的表达明显低于癌旁正常组织 (t=- 3 2 36 ,P <0 0 1) ,ERα/ERβ比值在人乳腺癌组织明显高于癌旁正常组织 (t =6 385 ,P <0 0 1) ;没有淋巴结转移的乳腺癌患者ERα/ERβ比值明显高于有淋巴结转移的乳腺癌患者 (t =2 6 0 2 ,P <0 0 5 ) ;在分期较晚的肿瘤ERα/ERβ比值明显低于分期较早的肿瘤 (t =3 75 4 ,P <0 0 5 )。结论　ERα在乳腺癌发生发展过程中与ERβ发挥不同的作用 ,并有可能成为乳腺癌基因治疗的新靶点。     

乳腺癌组织中PSAmRNA的表达及其与ER亚型表达的关系

目的 探讨前列腺特异抗原（PSA）mRNA和雌激素受体（ER）β亚型在乳腺癌组织中的表达及其与不同雌激素受体亚型表达之间的关系.方法 检测35例乳腺癌和12例癌旁乳腺组织及10例乳腺纤维腺瘤组织中的PSA mRNA和ERβ mRNA表达;35例乳腺癌组织ERα和PR蛋白的表达,并分析乳腺癌组织PSA mRNA表达与雌激素受体亚型和PR表达之间的关系.结果 PSA mRNA在乳腺癌组织中的表达水平明显低于癌旁乳腺组织和乳腺纤维瘤组织（P均=0.00）.ERβ mRNA在乳腺癌中的表达水平明显低于癌旁乳腺组织和乳腺纤维腺瘤组织（P均=0.00）.PSA mRNA表达阳性者ERβ mRNA表达水平明显低于PSA mRNA表达阴性者,差异有显著性（P=0.038）.ERα和PR阳性表达的乳腺癌组织中PSA mRNA表达高于ER和PR阴性者,差异有显著性（P=0.001,0.004）.结论 PSA和ERβ基因在乳腺癌中的表达下调.PSA可能是反映乳腺癌组织中功能性甾体类激素受体的一个重要指标.     

乳腺不典型增生和乳腺癌中p53、ER表达的意义

目的探讨p53基因产物和雌激素受体(ER)在乳腺不典型增生和乳腺癌中表达及意义。方法用ABC免疫组化法检测乳腺不典型增生和乳腺癌细胞p53基因产物和ER表达。结果乳腺上皮不典型增生Ⅰ级者上皮细胞ER染色结果与正常乳腺上皮细胞相似，不典型增生Ⅱ级ER表达明显增强，22／24例阳性，不典型增生Ⅲ级20／22例见ER染色阳性。在乳腺上皮不典型增生Ⅰ级无p53蛋白表达，不典型增生Ⅱ级、Ⅲ级中分别有3／24和7／22例p53蛋白表达。乳腺癌59例，ER阳性率为36／59(61．02％)。乳腺癌p53蛋白表达阳性22／59(37．29％)。结论p53可促进正常细胞以不典型增生向癌的转化，ER对不典型增生癌变起重要的刺激、激活作用。p53-／ER 代表正常组织、良性增生与高分化和好的预后，p53 ／ER-多为不典型增生、低分化癌和差的预后。所以同时检测p53、ER对判断不典型增生向癌的转化及乳腺癌患者的预后有重要意义。     

SDC-1在乳腺癌中的表达及其临床意义

目的 探究多配体蛋白聚糖-1 (Syndecans-1,SDC-1)在乳腺癌中的表达及其临床意义。方法 回顾性分析2021年1月至2021年6月本院收治的60例乳腺癌患者临床资料，收集乳腺癌患者术中切除的癌组织及经病理学检查未被浸润的癌旁正常乳腺组织，选用人正常乳腺上皮细胞系HBL-100和人乳腺癌上皮细胞系MCF-7，采用逆转录-聚合酶链式反应（RT-PCR）检测并比较HBL-100细胞和MCF-7细胞中SDC-1 mRNA相对表达量，采用Western Blot法检测并比较HBL-100细胞和MCF-7细胞中SDC-1蛋白表达量；采用免疫组织化学染色法检测并比较乳腺癌组织和癌旁正常组织中SDC-1阳性表达率，分析不同临床病理特征的乳腺癌患者癌组织中SDC-1阳性表达率，采用Spearman相关性分析SDC-1表达与乳腺癌临床病理特征的相关性。结果 人正常乳腺上皮细胞系HBL-100中SDC-1 mRNA、SDC-1蛋白相对表达量均高于人乳腺癌上皮细胞系MCF-7(P均<0.05)；乳腺癌组织和癌旁正常组织中SDC-1表达情况差异显著，且乳腺癌组织中SDC-1阳性表达率低于癌旁...     

抑癌基因PTEN在乳腺浸润性导管癌中的表达及临床意义

目的研究乳腺浸润性导管癌中PTEN蛋白表达与乳腺癌不同的临床病理因素、TNM分期的关系及其临床意义。方法采用免疫组织化学SP法,对32例乳腺浸润性导管癌组织中PTEN蛋白的表达水平进行检测。结果正常乳腺组织中PTEN表达阳性,32例乳腺癌中有13例PTEN阴性表达(41%),其中8例雌激素受体(ER)、孕激素受体(PR)阴性(61.5%),而19例PTEN阳性表达标本中仅4例ER、PR均为阴性(21.1%)。有腋淋巴结转移的乳腺浸润性导管癌组织中PTEN表达水平显著低于无腋淋巴结转移的乳腺浸润性导管癌组织(P<0.001);ER阴性者PTEN表达水平明显低于ER阳性者(P<0.05),PTEN表达水平与患者年龄、肿瘤大小、孕激素水平及临床分期无关,但随临床分期的增高,PTEN表达水平呈下降趋势。结论乳腺癌组织中PTEN蛋白失表达与腋淋巴结转移及雌激素阴性水平密切相关。     

ER△E5在乳腺癌组织中的表达及临床意义探讨

目的:通过检测乳腺癌和癌旁乳腺组织(乳腺癌标本边缘外5 cm)中雌激素受体a(Estrogen Receptor,ER a)剪切变异体ER△E5表达水平的差异,探讨ER△E5在乳腺癌组织中的表达及临床意义.方法:培养乳腺癌细胞株ZR-75-1,采用RT-PCR检测目的基因ER△E5,建立阳性对照体系.以液氮冷冻储存的59例乳腺癌组织和59例癌旁乳腺组织提取目的基因,进行对照实验,检测ER△E5在乳腺癌组织和癌旁乳腺组织中的表达状况,分析二者的表达差异及其临床意义.结果:在ER阳性乳腺癌标本中,ER△E5阳性20例(20/44),ER阴性的乳腺癌标本中,ER△E5阳性6例(6/15),两者差异无统计学意义(P=0.7170);在人表皮生长因子受体2(human epidermal growth factor receptor,HER-2)阳性的乳腺癌标本中,ER△E5阳性20例(20/22),HER-2阴性的乳腺癌标本中,ER△E5阳性6例(6/37).采用单因素分析,发现乳腺癌标本中ER△E5的阳性表达与HER-2的阳性表达呈正相关(P＜0.0001).在乳腺癌标本中ER△E5的阳性表达率为44.07%(26/59);在癌旁乳腺组织中未见ERAE5的表达,两者比较差异有统计学意义(P＜0.0001).在乳腺癌标本中ER△E5的表达与临床分期无相关性(P=0.9084).结论:在乳腺癌标本中ER△E5的表达显著高于癌旁乳腺组织,而且与HER-2表达呈正相关,提示ER△E5可能是一种新的临床预后的指标.     

酪氨酸激酶Syk基因在乳腺癌组织中的表达及其临床意义

目的　探讨酪氨酸激酶Syk基因表达与乳腺癌生成及转移的关系 ,以及与雌激素受体(ER)、孕激素受体 (PR)、p5 3、HER2 /neu基因的关系。方法　用半定量逆转录聚合酶链反应检测 4 0例乳腺癌患者癌组织及癌旁正常乳腺组织以及 15例良性乳房纤维瘤组织中SykmRNA的表达 ,并用免疫组化方法检测 4 0例乳腺癌组织中ER、PR、p5 3、HER2 /neu的表达的情况。结果　所有正常乳腺组织都有Syk基因的表达 ,而 4 0例乳腺癌组织中只有 9例表达 ,正常乳腺与乳腺癌组织中Syk基因表达率差异有显著意义 (χ2 =4 7 4 ,P <0 0 5 ) ,且乳腺癌组织中SykmRNA含量明显低于正常乳腺组织 (t =3 4 1,P <0 0 5 )。有淋巴结转移的 18例乳腺癌组织中 ,1例有Syk基因表达 ,有淋巴结转移的乳腺癌SykmRNA的表达率和表达水平显著降低 (χ2 =3 77,P <0 0 5 ,t=2 74 ,P <0 0 5 )。SykmRNA表达与 p5 3基因的表达呈正相关。 结论　Syk基因的表达在抑制乳腺癌的生长及转移过程中可能起着重要的作用     

ERΔE5在乳腺癌组织中的表达及临床意义探讨

目的：通过检测乳腺癌和癌旁乳腺组织（乳腺癌标本边缘外5cm）中雌激素受体α（Estrogen Receptor,ERα）剪切变异体ERΔE5表达水平的差异,探讨ERΔE5在乳腺癌组织中的表达及临床意义。方法：培养乳腺癌细胞株ZR-75-1,采用RT-PCR检测目的基因ERΔE5,建立阳性对照体系。以液氮冷冻储存的59例乳腺癌组织和59例癌旁乳腺组织提取目的基因,进行对照实验,检测ERΔE5在乳腺癌组织和癌旁乳腺组织中的表达状况,分析二者的表达差异及其临床意义。结果：在ER阳性乳腺癌标本中,ERΔE5阳性20例（20/44）,ER阴性的乳腺癌标本中,ERΔE5阳性6例（6/15）,两者差异无统计学意义（P=0.7170）;在人表皮生长因子受体2（human epidermal growth factor receptor,HER-2）阳性的乳腺癌标本中,ERΔE5阳性20例（20/22）,HER-2阴性的乳腺癌标本中,ERΔE5阳性6例（6/37）。采用单因素分析,发现乳腺癌标本中ERΔE5的阳性表达与HER-2的阳性表达呈正相关（P〈0.0001）。在乳腺癌标本中ERΔE5的阳性表达率为44.07%（26/59）;在癌旁乳腺组织中未见ERΔE5的表达,两者比较差异有统计学意义（P〈0.0001）。在乳腺癌标本中ERΔE5的表达与临床分期无相关性（P=0.9084）。结论：在乳腺癌标本中ERΔE5的表达显著高于癌旁乳腺组织,而且与HER-2表达呈正相关,提示ERΔE5可能是一种新的临床预后的指标。     

N-乙酰氨基半乳糖转移酶7在乳腺癌中的表达及临床意义

目的检测N-乙酰氨基半乳糖转移酶7(GALNT7)在乳腺癌与正常组织和细胞中的表达,并分析其表达水平与临床病理特征间的关系。方法采用实时定量反转录-聚合酶链反应(RT-QPCR)法检测GALNT7在40对乳腺癌组织和癌旁正常组织中的表达,运用Mann-Whitney法分析乳腺癌组织中GALNT7表达与患者临床病理特征之间的相关性。培养乳腺癌细胞株(MCF-7和MDA-MB-231)和正常乳腺上皮细胞株(MCF-10A)并采用实时荧光定量PCR方法检测GALNT7表达量。结果 GALNT7在乳腺癌组织中的相对表达量为1.09917±0.01756,癌旁正常组织为0.65218±0.07652,两组比较差异有统计学意义(P0.01),且乳腺癌组织中GALNT7表达量与患者ER受体表达呈负相关(P=0.016),与其他临床病理资料如年龄、肿瘤大小、PR和HER-2受体表达、临床分期及淋巴结转移无相关关系(P0.05)。GALNT7在乳腺癌细胞系中的表达量高于正常乳腺上皮细胞系(P0.001),且ER阴性乳腺癌细胞系MDA-MB-231的GALNT7表达量是ER阳性乳腺癌细胞系MCF-7的2.06倍(P0.05)。结论 GALNT7在乳腺癌组织和细胞株中均高表达,其在乳腺癌组织和细胞系中的表达与ER受体的表达密切相关,GALNT7与乳腺癌的发生发展相关。     

乳腺癌组织中survivin及其剪接体与VEGF的表达及临床意义

目的 研讨抗凋亡蛋白survivin及其剪接体survivin—△Ex3、survivin-2B与血管内皮生长因子（VEGF）在乳腺癌组织中表达情况及其与临床病理学指标的关系。方法以RT—PCR法检测100例乳腺癌及癌旁5cm正常乳腺组织标本中survivin及其剪接体survivin—△Ex3、survivin-2B与VEGF基因的mRNA表达,半定量分析电泳结果。以免疫组化法检测乳腺癌石蜡标本中的雌激素受体（ER）、孕激素受体（PR）和HER-2基因状态。结果Survivin及其剪接体survivin—△Ex3、survivin-2BmRNA在乳腺癌组织中均有较高表达,在癌旁5cm正常乳腺组织中均低表达,差异有统计学意义（P〈0．05）;VEGFmRNA在乳腺癌组织中均有较高表达,在正常乳腺组织中均低表达,差异有统计学意义（P〈0．05）;淋巴结转移与survivin-△Ex3、survivin-2B的表达相关（P〈0．05）。结论Survivin及其剪接体survivin—△Ex3、sur-vivin-2B与VEGF的表达与乳腺癌发生、发展有关,与其他预后指标ER、PR、HER-2等的联合检测可望对患者的预后作出更准确的预测。     

Roles of hormone replacement therapy and iron in proliferation of breast epithelial cells with different estrogen and progesterone receptor status

Estrogen and iron play critical roles in a female body development and were investigated in the present study in relation to in vitro cell proliferation. Prempro, a hormone replacement therapy drug, and 17beta-estradiol (E2) were shown to increase cell proliferations in estrogen receptor positive (ER+) cells independent of progesterone receptor (PR) status. For example, increased cell proliferation was observed in ER+/PR+ human breast cancer MCF-7, its matching non-cancerous human breast epithelial MCF-12A, and ER+/PR+ murine mammary cancer MXT+ cells, but not in ER-/PR- MDA-MB-231, its matching non-cancerous MCF-10A, and MXT- (ER-/PR+) cells. By mimicking post-menopausal conditions of high estrogen in local breast tissue and increased iron levels due to cessation of menstrual periods, E2 and iron were shown to exert synergistic effects on proliferation of MCF-7 cells and significantly increased Ki67 and proliferating cell nuclear antigen. Western blotting of E2-treated ER+ but not ER- cells showed that E2 also increased transferrin receptor (TfR). Further studies are needed to assess the mitogenic effects of iron and estrogen in normal post-menopausal breast.     

5氮2脱氧胞苷与三苯氧胺协同抗雌激素受体α阴性乳腺癌的体外实验研究

目的观察5氮2脱氧胞苷（5-aza—CdR）对雌激素受体α（ERα）阴性人类乳腺癌细胞株MDA—MB-231和MDA—MB-435ERα基因诱导表达作用;5-aza—CdR联合三苯氧胺（TAM）对ERα阴性乳腺癌细胞的体外抑制作用。方法应用甲基化特异性PCR（MSP）检测MDA—MB-231和MDA—MB-435细胞和20例ERα阴性乳腺癌组织ERα基因核心启动子区CpG岛甲基化情况;5-aza—CdR处理MDA—MB-231和MDA—MB-435细胞,逆转录PCR（RT—PCR）检测ERαmRNA表达;5-aza—CdR、TAM分别或联合作用于MDA—MB-231和MDA—MB-435细胞,M1T比色法分析细胞生长抑制作用,流式细胞仪测定细胞周期分布和凋亡率。结果适当浓度的5-aza—CdR能诱导MDA—MB-231和MDA—MB一435细胞表达ERctmRNA,抑制细胞生长、阻滞细胞周期于G0／G1期,诱导细胞凋亡;TAM对MDA—MB-231和MDA—MB-435细胞生长、细胞周期无影响;而两药联合时能显著抑制细胞生长,诱导细胞凋亡,凋亡率分别为48、8％和53、1％。结论5-aza—CdR能诱导ERα阴性乳腺癌表达ERctmRNA,恢复ERα阴性乳腺癌细胞对TAM的敏感性,联合TAM能协同抑制ERα阴性乳腺癌细胞生长,诱导细胞凋亡,从而为ERα阴性乳腺癌开辟新的内分泌治疗途径提供实验依据。     

Estrogen and Progesterone Receptors in Benign Breast Epithelium

Abstract: Estrogen and progesterone are necessary for lobulo-alveolar development of the human breast, and there is an abundance of epidemiologic literature implicating estrogen and possibly progesterone exposure as promoters of breast malignancy. The investigation of estrogen receptor (ER) and progesterone receptor (PgR) distribution in normal and benign breast tissue may be a measure of susceptibility of the tissue to these hormones. Earlier data from radioligand binding assays showed that benign breast tissue expressed little or no ER; newer immunohistochemical (IHC) methods have led to the investigation of benign breast tissue from at least 1243 women in 12 studies in the last 9 years. These show that the level of expression of ER and PgR in normal breast epithelium is significantly lower than in receptor positive carcinomas. Immunostaining patterns for both receptors show a great deal of heterogeneity. There is general agreement that stromal and myoepithelial cells are negative for both ER and PgR. A growing body of evidence suggests that PgR is the dominant sex steroid receptor in the normal breast. Mean values for PgR positive cells in breast epithelium range from 24% to 29%; ER is positive by IHC in 3% to 15.6% of normal breast epithelial cells. No firm conclusions are possible as yet regarding overexpression in proliferative epithelium. There is agreement that the proportion of ER positive cells declines in the second half of the menstrual cycle, but there is no clear cut relationship between PgR positivity with the menstrual cycle. Oral contraceptive use appears to decrease the proportion of ER positive cells, and increase mammary epithelial proliferation. A recent case-control analysis of epithelial ER and PgR status reports an association of ER positive benign epithelium with the presence of cancer in the breast. Future research should include a systematic quantitative analysis of receptor expression in epithelial proliferative lesions, and the longitudinal follow-up of women who have had receptor testing on benign breast tissue.     

雄激素受体在乳腺癌细胞中的表达及其对细胞增殖的影响

目的 检测雄激素受体(AR)在乳腺癌细胞中的表达,并观察雄激素刺激对乳腺癌细胞增殖的影响.方法 选择雌激素受体(ER)阳性的MCF-7和ER阴性的MDA-MB-453乳腺癌细胞,体外培养,Western blot技术检测两乳腺癌细胞株中AR蛋白的表达,MTT法检测用1×10-7、1×10-8和1×10-9 mol/L不同浓度的雄激素二氢睾酮(DHT)分别干预48、96、144 h后的细胞增殖,并应用流式细胞术检测DHT刺激乳腺癌细胞72 h后细胞周期的变化.结果 两个乳腺癌细胞株经DHT作用后AR蛋白表达均增多,DHT通过AR抑制MCF-7和MDA-MB-453两个乳腺癌细胞株的生长,各时间段不同浓度组比较A值差异无统计学意义(P＞0.05),细胞周期结果显示G1期细胞比例增高,S期细胞比例降低.结论 雄激素受体途径对ER阳性的MCF-7和ER阴性的MDA-MB-453乳腺癌细胞均有抑制生长作用,可能通过抑制细胞由G1期到S期转化来实现的.

Abstract：

Objective To evaluate the expression of androgen receptor (AR) in the breast cancer cell lines and its effect on proliferation of breast cancer cells. Methods The estrogen receptor (ER) -positive MCF-7 and ER-negative MDA-MB-453 cells were involved in this study and cultured in vitro. The expression of AR was detected by using Western blotting. Cell proliferation was determined by methyl thiazol tetrazolium (MTT) assay after the treatment with different concentrations of dihydrotestosterone (DHT) ( 1 x 10 -7, 1 x 10- 8, 1 x 10 -9 mol/L) for 48, 96 and 144 h respectively. Cell cycle was analyzed by flow cytometry following culture for 72 h. Results DHT increased the AR expression in the two breast cancer cell lines. AR pathway could inhibit proliferation of MCF-7 and MDA-MB-453 cells. There was no significant difference in absorbance values among three treatment groups at different time points (P ＞ 0. 05). Cell cycle analysis revealed that the proportion of cells at G1 phase was increased, and that at S phase decreased. Conclusion AR pathway may inhibit proliferation of ER-negative MDA-MB-453 breast cells as well as ER-positive MCF-7 cells, by suppressing the process of G1 to S phase progression.     

雌激素受体亚型在肥大乳房乳腺组织中的表达及意义

目的:研究雌激素受体亚型α和β(ERα和ERβ)在肥大乳房乳腺组织中和正常体积乳房乳腺组织中的表达,探讨其在乳房肥大发病机制中的作用和意义.方法:采用免疫组织化学EnVision二步法,测定38例肥大乳房和17例正常体积乳房中ERα和ERβ的表达情况.结果:ERα在肥大乳房和正常体积乳房中的阳性表达率分别为97.37%和76.47%,两者比较差异具有统计学意义(P<0.05).ERβ在肥大乳房和正常体积乳房中的阳性表达率分别为89.47%和100%,两者比较差异无统计学意义(P>0.05).结论:乳房肥大的发生可能与乳腺组织中ERα含量升高有关,与ERβ无明显相关性.     

A Novel Effect of β-Adrenergic Receptor on Mammary Branching Morphogenesis and its Possible Implications in Breast Cancer

Understanding the mechanisms that govern normal mammary gland development is crucial to the comprehension of breast cancer etiology. β-adrenergic receptors (β-AR) are targets of endogenous catecholamines such as epinephrine that have gained importance in the context of cancer biology. Differences in β₂-AR expression levels may be responsible for the effects of epinephrine on tumor vs non-tumorigenic breast cell lines, the latter expressing higher levels of β₂-AR. To study regulation of the breast cell phenotype by β₂-AR, we over-expressed β₂-AR in MCF-7 breast cancer cells and knocked-down the receptor in non-tumorigenic MCF-10A breast cells. In MCF-10A cells having knocked-down β₂-AR, epinephrine increased cell proliferation and migration, similar to the response by tumor cells. In contrast, in MCF-7 cells overexpressing the β₂-AR, epinephrine decreased cell proliferation and migration and increased adhesion, mimicking the response of the non-tumorigenic MCF-10A cells, thus underscoring that β₂-AR expression level is a key player in cell behavior. β-adrenergic stimulation with isoproterenol induced differentiation of breast cells growing in 3-dimension cell culture, and also the branching of murine mammary epithelium in vivo. Branching induced by isoproterenol was abolished in fulvestrant or tamoxifen-treated mice, demonstrating that the effect of β-adrenergic stimulation on branching is dependent on the estrogen receptor (ER). An ER-independent effect of isoproterenol on lumen architecture was nonetheless found. Isoproterenol significantly increased the expression of ERα, Ephrine-B1 and fibroblast growth factors in the mammary glands of mice, and in MCF-10A cells. In a poorly differentiated murine ductal carcinoma, isoproterenol also decreased tumor growth and induced tumor differentiation. This study highlights that catecholamines, through β-AR activation, seem to be involved in mammary gland development, inducing mature duct formation. Additionally, this differentiating effect could be resourceful in a breast tumor context.     

Biological effect of estrogen metabolites in human breast cancer]

In order to investigate the estrogen metabolism in human breast cancer, the estradiol 2- and 16 alpha-hydroxylase (2-, 16 alpha-OHase) activities were determined in the microsomal fractions of human breast tissues by using reverse-phase HPLC. The effects of estrogen metabolites on the cell proliferation were also examined by employing two human breast cancer cell lines. The 2-OHase activity was detected in most cancerous and noncancerous tissues, but the value in cancerous tissues was significantly lower than that in noncancerous tissues (p less than 0.05). Patients without lymph node metastases showed relatively higher activity than those with metastases (0.05 less than p less than 0.1). The 16 alpha-OHase activity was, however, found in only 23% of cancerous tissues. Among those, the activity was present in 52% of ER positive cancerous tissues, but almost absent in ER negative ones. The growth ER positive cell line, MCF-7, was suppressed with 2-hydroxyestrone and stimulated with 16 alpha-hydroxyestrone. The cell proliferation stimulated with 16 alpha-hydroxyestrone was not inhibited by the addition of tamoxifen, a strong antagonist of estradiol. Two metabolites had no effect on the growth of ER negative cell line, MDA-MB-231. These results suggest that estrogen metabolites influence the proliferation of human breast cancer cells as the endogenous regulatory factors and should be considered for the future endocrine therapy.     

Effect of combined oral contraceptives on breast epithelial proliferation in young women

The mammary gland undergoes morphologic changes during the menstrual cycle. Proliferation of normal breast epithelium is most extensive during the natural luteal phase. To determine the impact of one cycle of a combined oral contraceptive (COC) on breast homeostasis, we evaluated the proliferation index (PI), determined by KI-67 expression, in normal human mammary epithelial cells and correlated it with cellular proliferation in spontaneous menstrual cycles during the same period. Normal breast tissue samples were obtained from 82 patients randomized in two groups. Forty-two women in group A received one cycle of a COC (30 mug ethinyl estradiol and 150 mug levonorgestrel) administrated daily for 21 days, beginning on the first day of the menstrual cycle. Group B patients (n = 40) experienced a natural menstrual cycle. Menstrual cycle phase characterization was based on the date of the last period and subsequent menses and on progesterone serum levels obtained at the time of biopsy. The PI (number of Ki-67-positive nuclei per 1,000 epithelial cells), was significantly larger in group A (5.47 +/- 3.87), than in group B (3.27 +/- 3.24), p < 0.01. A cyclical variation of PI was observed in COC cycles. The rise in PI in the first week of the COC cycles was significantly higher than in the natural cycle (COC = 7.02 +/- 4.94; non-COC = 1.10 +/- 0.67; p < 0.0011). There was no significant difference between the two groups during the other weeks. Additionally, there was an inverse correlation between proliferation and chronological age, irrespective of the stage of the cycle. The PI of COC (p = 0.175) and natural cycles (p = 0.466) were not statistically different in younger patients. COC users have increased proliferative activity at the beginning of the menstrual cycle. This alteration in the pattern of proliferative activity may relate to the increased risk of breast cancer that has been associated with COCs.     

Changes in the hormone dependency of DMBA-induced rat mammary tumors with reference to the effect of tamoxifen

Tamoxifen was administered over a period of 4 weeks to 19 female Sprague-Dawley rats bearing 20 DMBA-induced mammary tumors. Consequently, 13 tumors (65.0 per cent) regressed and showed a reduction in their estradiol receptor (ER) and progesterone receptor (PgR) concentrations. In spite of subsequent treatment given to the rats bearing the regressed tumors, 6 new tumors occurred. The ER and PgR concentrations of these tumors were lower than those of the tumors before tamoxifen therapy, and histochemical study showed these tumors to be composed mostly of ER-negative cells. These results suggest that: (a) the hormone dependency of breast cancer is reduced by tamoxifen therapy; (b) breast cancers recurring during tamoxifen therapy show reduced hormone dependency.     

The Cell of Origin of <Emphasis Type="Italic">BRCA1</Emphasis> Mutation-associated Breast Cancer: A Cautionary Tale of Gene Expression Profiling

Breast tumours are highly heterogeneous with several distinct sub-types recognised according to their histological and molecular features. The biological basis for this heterogeneity is largely unknown, although there are some distinct phenotype–genotype correlations. These include BRCA1 mutation-associated breast cancers, which are typically high grade invasive ductal carcinomas of no special type (IDC-NSTs) with pushing margins that do not express estrogen receptor (ER), progesterone receptor (PR) or the HER2 receptor tyrosine kinase (‘triple negative’). Gene expression analysis of these tumours has grouped them with so called ‘basal-like’ breast cancers and this, together with evidence that knock-down of BRCA1 in vitro blocked luminal differentiation, led to speculation that these tumours arose from the normal basal stem cells within the mammary gland. Recently, however, human breast tissue from BRCA1 mutation carriers was shown to contain an expanded population of luminal progenitor cells which have increased in vitro clonogenic ability. In the mouse, targeted deletion of Brca1 in luminal ER negative progenitors resulted in the formation of mammary tumours which phenocopied human BRCA1 breast tumour pathology, while the deletion of Brca1 in basal stem cells resulted in the formation of tumours which neither resembled human BRCA1 tumours or sporadic basal-like breast tumours. Importantly, however, both sets of mouse tumours were classified as ‘basal-like’ by methods used for human tumour classification based on gene expression profiles. This demonstrates that, as it stands, expression profiling is poor at distinguishing tumour histological subtypes and is also a poor guide to the cell of tumour origin. These human and rodent studies support an origin of BRCA1-mutation associated breast cancer (and indeed of the majority of sporadic basal-like breast cancers) in a luminal ER negative mammary epithelial progenitor. This is a key finding, as identification of the cells of origin in breast cancer subtypes makes possible the identification of key processes associated with initiation, progression and maintenance of each tumour subtype, the development of novel targeted therapies and, potentially, of new preventative approaches in high risk groups.