干扰素/维甲酸联合应用诱导细胞凋亡相关基因-19在小鼠围着床期子宫内膜中的表达及其作用

目的 探讨干扰素/维甲酸联合应用诱导细胞凋亡相关基因-19（GRIM-19）在小鼠围着床期子宫内膜中的表达及其与胚胎着床的关系。方法 收集早期妊娠第1~6天小鼠子宫组织,采用免疫组织化学法检测GRIM-19蛋白在子宫内膜上皮细胞中的表达及定位情况;收集早期妊娠、假孕和雌孕激素处理小鼠子宫组织,采用Western blotting 和Real-time PCR检测GRIM-19蛋白和mRNA水平;TUNEL方法检测早期妊娠第1~6天小鼠子宫组织细胞凋亡情况;采用pEGFP GRIM-19质粒GRIM-19-siRNA 转染技术使RL95-2细胞系过表达或低表达GRIM-19,检测其对RL95-2-BeWo 共培养体外着床模型球状体黏附率的影响,AnnexinV/PI双染色法检测细胞凋亡,线粒膜电位检测试剂盒（JC-1）检测线粒体跨膜电位;采用Western blotting 和Real-time PCR检测转染后信号转导子和转录激活因子3（STAT3）、肿瘤坏死因子（TNF)-α及白细胞介素（IL)-11蛋白和mRNA水平。结果 GRIM-19在早期妊娠第1~6天小鼠子宫腔上皮和腺上皮均有表达,妊娠第4天GRIM-19蛋白和mRNA水平减低,细胞凋亡减少;假孕第1~6天小鼠子宫内膜GRIM-19表达无明显差异;雌激素处理组小鼠子宫内膜GRIM-19表达减弱;过表达GRIM-19后,RL95-2-BeWo 共培养球状体黏附率降低,细胞凋亡增加,线粒体膜电位减低,RL95-2细胞系中STAT3及IL-11蛋白和mRNA水平减低,TNF-α蛋白和mRNA水平升高。 结论 GRIM-19在胚胎着床中发挥重要作用,可能是通过调节细胞凋亡和免疫耐受为胚胎着床提供保障。     

雌、孕激素对LPA3在小鼠子宫内膜围着床期表达的影响

目的 研究小鼠围着床期子宫内膜溶血磷脂酸受体3（LPA3）的表达以及雌、孕激素和孕激素拮抗剂RU486对其表达的影响。方法 用免疫组化法,检测妊娠第1~6天（d1~6）小鼠子宫内膜LPA3蛋白的表达规律; 用RT-PCR、Western blot检测子宫内膜LPA3的表达。结果 妊娠第1~6天小鼠子宫内膜组织均有LPA3表达,d3表达开始增强,d4最强,d5和d6 表达骤然下降。去势小鼠子宫内膜表达低水平LPA3 ;孕激素提高子宫内膜LPA3 的表达,且呈时间依赖性。雌激素对LPA3 表达无明显影响。雌、孕激素联合应用,雌激素降低孕激素对子宫内膜LPA3 表达的上调作用。RU486减弱孕激素的上调作用。结论　LPA3可能参与了胚胎的种植。雌、孕激素可能通过影响小鼠子宫内膜LPA3 的表达,共同参与小鼠子宫内膜容受性的建立。     

小鼠胚泡植入早期FucT-Ⅶ和sLe(X)寡糖抗原表达

目的探讨妊娠第1～5天(d1～5)小鼠子宫内膜唾液酸化的路易斯寡糖[sLe(X)]合成关键酶α-1,3岩藻糖基转移酶基因(FucT-Ⅶ)的表达和其表面sLe(X)寡糖抗原表达对胚胎植入的影响。方法应用RT-PCR和免疫组化方法检测妊娠第1～5天小鼠子宫内膜FucT-Ⅶ及寡糖抗原的表达规律。用子宫角内注射sLe(X)单克隆抗体的方法检测小鼠胚胎着床数。结果妊娠第1～5天小鼠子宫组织均有FucT-Ⅶ的表达,且在妊娠d4表达更强(P<0.05)。妊娠第1～5天sLe(X)寡糖抗原表达在子宫内膜的腔上皮和腺上皮。单侧子宫角sLe(X)抗体注射后胚胎的着床数量明显较对侧(注射等体积生理盐水)减少。结论在小鼠胚胎着床过程中,FucT-Ⅶ及sLe(X)寡糖抗原可能参与了胚泡的定位、黏附及侵袭过程,在胚泡植入的早期发挥作用。     

孕酮拮抗物RU486对妊娠小鼠子宫巨噬细胞的影响及与妊娠相关性的研究

目的　研究孕酮拮抗物RU4 86对妊娠小鼠子宫巨噬细胞的影响及与妊娠的相关性。　方法　取孕4、10d的小鼠 ,皮下注射RU4 86 (每只 15 0mg L) ,对照组以等量生理盐水代替。在注射后 12、2 4、36h密切观察妊娠结果 ,并用免疫组织化学方法检测子宫内的巨噬细胞。　结果　孕 4d ,注射RU4 86可以完全阻止胚泡的着床 ,且注射后 12～ 36h有大量的巨噬细胞涌入子宫内膜、肌层和肌间血管层 ,细胞数量极显著地高于对照组 (P <0 0 0 1)。孕 10d ,RU4 86处理可以导致大多数胚胎吸收 ,并在处理后 4～ 36h子宫巨噬细胞的数量和分布发生急剧的变化 ,尤其是 12～ 36h细胞数量极显著地高于对照组 (P <0 0 0 1)。　结论　RU4 86诱导小鼠妊娠早期的着床失败和妊娠中期的胚胎吸收与大量巨噬细胞侵入子宫有密切的关系 ,拮抗孕酮的免疫抑制功能可能是RU4 86的抗孕机制之一     

超数排卵对小鼠妊娠建立的影响

目的 探讨超数排卵(超排)是否通过改变小鼠子宫内环境影响小鼠妊娠建立过程。方法 对比超排小鼠和自然交配小鼠着床妊娠情况，建立超排移植小鼠研究模型，在0.5 d将超排小鼠一侧输卵管结扎，2.5 d通过手术法向结扎侧子宫角移植正常囊胚，比较两侧子宫角的妊娠着床情况。通过组织切片和高通量测序方法对比超排假孕小鼠和正常假孕小鼠着床前子宫的差异，并进行生物学分析。结果 与正常小鼠相比，超排小鼠的妊娠率显著下降，超排组妊娠个体的平均着床数高于对照组。超排移植小鼠的对照侧与移植侧子宫角妊娠率之间差异不显著。超排假孕小鼠子宫内膜变薄，腺体数量减少。超排假孕和正常假孕小鼠着床前子宫的基因表达模式存在差异，显著差异基因1097个，其中上调基因752个，下调基因345个。生物信息学分析显示，差异基因在生物学过程中主要参与蜕膜化、对孕激素的反应、血管生成的正向调节等过程，主要富集在FoxO信号通路、细胞周期信号通路和类固醇生物合成信号通路上。结论 超数排卵处理影响了小鼠妊娠的建立，改变了小鼠着床前子宫容受性相关标志基因的表达。     

白细胞介素8在着床前小鼠子宫及胚卵的表达

目的:观察着床前小鼠子宫及胚卵白细胞介素8(IL-8)的表达.方法:免疫组织化学显色及图像分析技术,对IL-8蛋白在妊娠1～4 d小鼠子宫及胚卵的表达进行定位及半定量分析;用RT-PCR技术检测妊娠1～4 d小鼠子宫及胚卵IL-8mRNA的表达情况.结果:与未孕小鼠相比,妊娠各天小鼠子宫中IL-8蛋白和mRNA表达明显升高,于妊娠4d表达最强.IL-8蛋白和mRNA均在妊娠2 d(Ⅱ细胞期)的胚卵表达最弱,妊娠4d(胚泡期)的胚卵表达最强.结论:妊娠1～4 d小鼠子宫及胚卵持续表达IL-8蛋白和mRNA,尤其是在着床前表达量升高,提示它们可能参与小鼠胚泡的着床过程.     

妊娠早期小鼠卵巢、输卵管及子宫内诱导型一氧化氮合酶的分布

目的　了解胚泡着床前后妊娠昆明系小鼠卵巢、输卵管及子宫内诱导型一氧化氮合酶 (inducible ni-tric oxide synthase,i NOS)的分布。　方法　免疫细胞化学 L SAB法。　结果　妊娠 2～ 5 d小鼠的卵巢内 ,黄体细胞上有 i NOS的阳性表达 ;输卵管粘膜上有 i NOS的分布 ,肌层则为阴性 ;妊娠 2、3d的小鼠子宫内 ,阳性标记主要出现在子宫内膜上皮以及子宫内膜中的子宫腺上皮 ,内膜基质细胞为阴性 ;妊娠 4d的子宫内 ,子宫腺及蜕膜部分均有 i-NOS的分布 ,妊娠 5 d时 ,在小鼠胚泡的表面也检测到了 i NOS的存在。　结论　小鼠胚泡着床前后 ,在其卵巢、输卵管及子宫内均有 i NOS的存在 ,提示 i NOS在小鼠胚胎早期发育及着床过程中起作用。     

子宫内膜基质细胞AQP7的表达以及卵巢激素对AQP7的调控作用

目的:探讨水通道蛋白7(Aquaporin 7,AQP7)在小鼠子宫内膜及在体外诱导蜕膜化模型中的表达,卵巢激素对AQP7的调控,以探讨AQP7在子宫蜕膜化中的作用.方法:分离孕4-8天小鼠子宫基质细胞(Uterine stromal cells,ESCs),实时定量PCR(RT-PCR)检测基质细胞AQP7表达.收集孕4～8天小鼠子宫,免疫组织化学染色检测子宫内膜组织AQP7的表达.分离原代小鼠基质细胞,建立体外诱导蜕膜化模型,RT-PCR检测AQP7在ESCs中的表达.在体外培养的孕5天小鼠子宫基质细胞中分别加入雌二醇(E2)、孕酮(P4)以及E2和P4联合处理.用雌激素受体(ER)的拮抗剂ICI 182,780和孕激素受体(PR)拮抗剂RU486预处理基质细胞,再用E2+P4处理.收集各组ESCs,RT-qPCR检测卵巢激素对基质细胞中AQP7的调控作用.结果:AQP7 mRNA在体外分离的孕4～8天的子宫基质细胞中的表达逐渐升高.从孕5～8天,随着蜕膜化进程,子宫基质细胞中AQP7表达也逐渐增加.在体外诱导蜕膜化模型中,小鼠基质细胞中AQP7 mRNA表达显著升高(P<0.01).在E2和P4单独作用下,基质细胞中AQP7表达无明显变化;而与对照组比较,E2和P4联合处理组在E2和P4联合作用24小时后基质细胞中AQP7表达显著升高(P<0.01);且在E2和P4联合作用后、基质细胞中AQP7的升高能够被雌激素受体的拮抗剂ICI 182,780和孕激素受体拮抗剂RU486阻断(P<0.01).结论:随着蜕膜化进程,子宫基质细胞中AQP7表达逐渐增加.卵巢雌、孕激素联合作用可上调基质细胞中AQP7表达.子宫基质细胞中AQP7在蜕膜化和胚胎着床中发挥着重要作用.     

Effect of estrogen and progestogen on the expression of interleukin-8 in mouse endometrium and blastocyst during preimplantation

目的:研究雌、孕激素对着床前小鼠子宫内膜及胚泡白细胞介素8(IL-8)表达的影响.方法:利用经典小鼠胚泡延迟着床模型,应用免疫组织化学显色、免疫印迹及图像分析技术,对着床前小鼠子宫内膜及胚泡IL-8的蛋白表达进行定位及半定量分析.结果:IL-8主要表达于妊娠小鼠子宫内膜腔上皮细胞及胚泡内细胞群和滋养层细胞的细胞质内.在子宫内膜组织中,切除双侧卵巢后单独给予孕酮组(P4组),IL-8表达低于联合应用雌二醇和孕酮组(E2+P4组)和对照组;E2+P4组IL-8表达上调,但低于对照组.在各组胚泡中,单独给予孕酮获得的静止胚泡、IL-8蛋白含量低于正常胚泡;联合应用雌二醇、孕酮获得的激活胚泡、IL-8的蛋白表达高于静止胚泡.结论:切除卵巢后,联合应用雌、孕激素可上调着床前小鼠子宫内膜及胚泡IL-8蛋白的表达.     

整合素α4、β1 mRNA在着床前小鼠子宫内膜及胚卵的表达

目的 观察着床前小鼠子宫内膜及胚卵整合素α4、β1mRNA的表达。方法 用原位杂交技术检测妊娠1～4d小鼠子宫内膜及胚卵整合素α4、β1mRNA的表达。结果 整合素α4、β1mRNA主要表达在子宫内膜腔上皮，腺上皮，表达强弱不等。妊娠3d基质细胞出现阳性信号，4d增强；胚卵整合素α4、β1mRNA仅在Ⅱ细胞期弱表达，在其他时期表达较强。结论 妊娠1～4d小鼠子宫内膜及胚卵持续表达整合素α4、β1mRNA，提示它们可能参与小鼠胚泡的着床过程。     

Mifepristone (Ru486) antagonizes monocyte chemotactic protein-3 down-regulation at early mouse pregnancy revealing immunomodulatory events in Ru486 induced abortion

PROBLEM: The survival of an embryo bearing the paternal antigens within the immunocompetent environment of the maternal uterus renders 'pregnancy' to be a state of immunological paradox. The ratio of Th1/Th2 responses is crucial for pregnancy maintenance. Monocyte Chemotactic Protein-3 (MCP3) is a pro-inflammatory, CC chemokine and a Th1 effector which is capable of eliciting significant anti-tumoral immune responses. METHOD OF STUDY: MCP3 expression was investigated in the murine uterine tissue at different days of initial pregnancy and the effect of RU 486 in immature and delayed implantation model studied using Western blotting and Immunocytochemical techniques. RESULTS AND CONCLUSION: Our results show very high uterine MCP3 expression during pre-implantation followed by a significant MCP3 down-regulation at peri-implantation and low levels of MCP3 during post-implantation period. At the peri-implantation stage, embryos exhibited lowered MCP3 expression when compared with the pre-implantation stage. Ru486, a progesterone antagonist when given in a competitive mode with progesterone resulted in a massive surge in MCP3 expression in both immature mice and delayed implantation models. We hypothesize that it is imperative for MCP3 expression to be down-regulated for the success of pregnancy. The cross-talk between Ru486 and amplified MCP3 expression may be one of the mechanisms by way of which RU486 performs its abortificient and anti tumor role.     

Hormone allergy

BACKGROUND: Estrogen and progesterone have been associated in women with symptoms that include asthma, migraine, dermatitis and pain. OBJECTIVE: We suggest a connection between symptoms associated with hormone changes to a hormone antibody response. METHODS: For IgG, IgM and IgE antibodies to progesterone, blood samples were obtained from 288 healthy control subjects by a commercial lab in California. Blood from 270 patients in Texas with changes in symptoms associated with menstrual cycles was examined. For IgE antibodies to both progesterone and estrogen, blood samples were obtained from an additional 32 healthy control subjects who had no symptoms related to menses and from 98 patients with symptoms associated with menstrual cycles. The symptoms were asthma, migraines and joint pain. RESULTS: At 2 S.D. above the mean values of control subjects, a significant number of patients show high levels of IgG, IgM and IgE antibodies to progesterone and estrogen. CONCLUSIONS: This paper describes evidence of antibodies to the hormones estrogen and progesterone. Progesterone, estrogen and their metabolites, after binding to human tissue proteins, such as albumin or globulin, may act as antigens and promote Type 2 helper cell development, thereby regulating antibody synthesis and allergy. This leads to the possibility of treating a wide variety of disorders by determining hormone allergy and initiating desensitization. Two obvious applications for determination and treatment of hormone allergies are pre-menstrual asthma and menstrual migraines.     

Anti-nidatory effect of a single, early post-ovulatory administration of mifepristone (RU 486) in the rhesus monkey

The hypothesis that post-coital administration of mifepristone(RU 486) as a single dose in the early luteal phase can be aneffective anti-nidatory strategy was tested using the rhesusmonkey as the experimental model. Incidence of pregnancy, vaginalbleeding patterns, profiles of menstrual cyclicity and of serumlevels of progesterone and oestrogen were examined followingadministration of RU 486 as a single dose of 10 mg/kg and 2mg/kg body weight on the second day after ovulation. In controlmonkeys (group 1; n = 5) receiving the vehicle alone (benzylbenzoate: olive oil, 1: 4, v/v) there was a 60% pregnancy rate.Following s.c. administration of RU 486 at both doses, no pregnancywas recorded in a total of 33 treatment cycles in 12 monkeys.Five monkeys received RU 486 at 10 mg/kg s.c. (group 2) in threeconsecutive cycles. All animals had complete inhibition of implantation;in addition, the treatment cycle length was prolonged (P <0.001) due to an extension of the luteal phase. The subsequentfollicular phase was unaffected. Mild, premature vaginal bleedingduring the luteal phase was recorded in five treatment cycles,3–5 days after drug application. Though the serum profilesof progesterone and oestrogen in these monkeys showed markedindividual variations, there was a characteristic progesteronerebound about 18–20 days after drug administration. Monkeysin group 3 were given RU 486 at 2 mg/kg, s.c. either for threeconsecutive cycles (group 3a; n = 4) or for two consecutivecycles (group 3b; n = 3). Premature luteal phase vaginal bleedingoccurred only in four treatment cycles, within 2–6 dayspost-treatment. An increase in both the duration (P < 0.001)and degree (P < 0.001) of menstrual flow as compared withthe pre-treatment cycles was recorded in six treatment cyclesof three monkeys in group 3. These animals did not have prematureluteal phase vaginal bleeding. Collectively, 100% protectionagainst pregnancy with no change in the cycle length was obtainedin all seven monkeys in 18 treatment cycles. Analysis of pooleddata revealed that the subsequent follicular phase, as wellas the ovarian steroid hormone profiles of treatment cycleswere unaffected. Thus, a single application of RU 486 in theearly secretory phase appears to be a potential anti-implantationstrategy for intercepting pregnancy in the primate.     

Role of estrogen and progesterone in the regulation of uterine peristalsis: results from perfused non-pregnant swine uteri

BACKGROUND: Adequate uterine contractility and peristalsis are involved in the transport of semen and gametes and in successful embryo implantation. Estrogen and progesterone fluctuate characteristically during the menstrual cycle. It has been suggested that both hormones influence uterine peristalsis in characteristic ways. METHODS: An extracorporeal perfusion model of the swine uterus was used that keeps the uterus in a functional condition and is suitable for the study of physiological questions. The effects of estrogen and progesterone on oxytocin-induced uterine peristalsis were assessed using an intrauterine double-chip microcatheter. RESULTS: Estrogen perfusion was associated with an increase in intrauterine pressure (IUP) in a dose-dependent manner. There was a significant difference between the IUP increase measured in the isthmus uteri and that in the corpus uteri, resulting in a cervico-fundal pressure gradient. Estrogen perfusion resulted in a significantly higher rate of peristaltic waves starting in the isthmus uteri and directed towards the corpus uteri. Progesterone was able to antagonize the estrogen effect in general. CONCLUSIONS: This study demonstrates that estrogen and progesterone have differential effects in the regulation of uterine peristalsis. The present observation shows that estrogen stimulates uterine peristalsis and is able to generate a cervico-fundal direction of peristalsis, whereas progesterone inhibits directed uterine peristalsis.     

Uteroglobin as a progesterone-binding protein in the preimplantation uterine epithelium of the rabbit: biochemical studies

Progesterone binding was studied in the uterus of rabbits attwo different hormonal stages; either after oestrogen primingor a short time before implantation of the blastocyst (162 hpost coitum). Uterine cytosols were incubated with [³H]progesterone,or the labelled hormone was injected into the uterine lumen1 h before killing the animals. Gel filtration, ion exchangechromatography, sucrose gradient centrifugation, isoelectricfocusing and saturation analysis indicate that during the periodprior to implantation, the uterine progesterone receptor disappearsand progesterone binding is performed by uteroglobin. Thesefindings support the hypothesis that the physiological roleof uteroglobin in the reproductive process is connected withits hormone-binding ability.     

宫腔灌注人绒毛膜促性腺激素改善多囊卵巢综合征患者子宫内膜容受性

目的探讨宫腔灌注人绒毛膜促性腺激素(hCG)对多囊卵巢综合征(PCOS)患者子宫内膜容受性、雌孕激素及其受体的影响。方法对照组(n=23)为健康女性,研究组为PCOS患者。研究组1(n=25)给予口服来曲唑;研究组2(n=20)口服来曲唑同时于排卵前2日及排卵日分别给予hCG 500 IU/mL宫腔灌注1次。各组均于排卵后第6~8天抽取子宫内膜,行免疫组织化学染色检测雌激素受体(ER)及孕激素受体(PR)的表达;扫描电镜(SEM)观察子宫内膜胞饮突;于取内膜当日用化学发光法检测血清雌激素(E2)和孕激素(P)的浓度;于排卵后16 d计算各组妊娠率。结果研究组1成熟期胞饮突的表达率低于对照组,研究组2成熟期胞饮突的表达率高于研究组1(P<0.05)。研究组1着床窗期P水平、子宫内膜PR阳性表达率均低于对照组,研究组2着床窗期P水平、子宫内膜PR阳性表达率均高于研究组1(P<0.05)。研究组1妊娠率低于对照组,研究组2妊娠率高于研究组1(P<0.05)。结论PCOS患者着床窗期胞饮突发育不良;宫腔灌注hCG可能使成熟期胞饮突数量增加,改善子宫内膜容受性,其机制可能与P水平升高、PR表达增加有关。     

Differential Expression and Regulation of Angiopoietin‐2 in Mouse Uterus During Preimplantation Period

Angiogenesis is crucial to successful implantation and decidualization, however, as an important angiogenic growth factor, the effect of Ang‐2 in the process of implantation and decidualization is still unknown. This study is to investigate the differential expression of Ang‐2 in mouse uterus during early pregnancy and its regulation by steroid hormones using in situ hybridization and RT‐PCR. There is no detectable Ang‐2 mRNA signal on days 1–5 of pregnancy by in situ hybridization. On days 6–8, Ang‐2 mRNA is mainly expressed in the primary decidua of mesometrial side, and the expression gradually increases. By RT‐PCR, a significantly higher level of Ang‐2 expression is observed on day 8 of pregnancy, although Ang‐2 expression can be found through days 1–8. Similarly, Ang‐2 is highly expressed in decidualized cells under artificial decidualization. In the ovariectomized mouse uterus, Ang‐2 expression gradually increases after estrogen injection and with peak levels at 12 hr, while progesterone injection can cause a decline in uterine Ang‐2 mRNA level, which reaches a nadir at 12 hr. These results suggest that Ang‐2 may play a key role in the process of mouse decidualization. Estrogen can induce the expression of Ang‐2 while progesterone can inhibit its expression in the ovariectomized mouse uterus. Anat Rec, 2012. © 2011 Wiley Periodicals, Inc.     

Modulation of nerve growth factor in peripheral organs by estrogen and progesterone

Nerve growth factor (NGF) synthesized in peripheral organs plays a critical role in the development and maintenance of the nervous system and also participates in processing nociceptive stimuli. Previous studies suggest that reproductive hormones may regulate the expression of NGF. Ovariectomies were performed on female mice, and mice were killed 24 h after hormone replacement to evaluate the effects of estrogen and progesterone on NGF in peripheral organs, specifically the uterus, bladder, heart, and salivary gland. Sham-operated intact mice and untreated ovariectomized mice served as controls. Immunohistochemistry demonstrated the presence of NGF, estrogen receptor-alpha, estrogen receptor-beta, and progesterone receptors in these organs. Ovariectomy caused a significant decrease in NGF protein content in the uterus, and short term treatment of ovariectomized mice with estrogen and/or progesterone increased uterine NGF mRNA and restored NGF protein to concentrations similar to intact control mice. Ovariectomy did not affect NGF protein concentrations in the salivary gland, but treatment of ovariectomized mice with estrogen alone or in conjunction with progesterone stimulated concentrations of NGF protein that exceeded those observed in intact control or ovariectomized, untreated mice. NGF mRNA was increased in salivary glands from ovariectomized mice treated with progesterone alone or in combination with estrogen relative to other groups. NGF protein content of the hearts of ovariectomized mice treated with estrogen alone or in conjunction with progesterone was increased relative to intact controls and ovariectomized, untreated mice, but neither ovariectomy or hormone replacement affected NGF mRNA content in the heart. NGF protein content of the bladder was unaffected by ovariectomy or hormone treatment, and bladder NGF mRNA was unaffected by ovariectomy or hormone treatment. Collectively, these results indicate that reproductive hormones have the capacity to regulate NGF message and protein in a manner that varies among organs. Fluctuations in the expression of NGF, in conjunction with other factors, may help to explain gender differences in pain sensation and inflammatory response.     

High Expression of the Trefoil Protein TFF1 in Interval Breast Cancers

Breast cancer screening is important for the early detection of breast cancer. Tumors that become symptomatic in the screening interval are known as interval cancers but the reasons for their rapid progression are unknown. Estrogen receptor expression is lower in interval cancers suggesting that they may have reduced hormonal responsiveness. To investigate this hypothesis we have measured the expression of the estrogen receptor and three estrogen-responsive genes (cathepsin D, progesterone receptor, and TFF1) in screen-detected and interval breast cancers. The expression of the protease cathepsin D was not associated with estrogen receptor in either group of tumor. Progesterone receptor expression was highly correlated with that of the estrogen receptor in both groups of tumors but it was not expressed at significantly different levels in the two groups of tumors. Expression of TFF1, a cellular motogen, was correlated with estrogen receptor in screen-detected but not interval cancers and was expressed at markedly higher levels in interval breast tumors, the group that expresses lower levels of estrogen receptor. Interval cancers are characterized by high levels of expression of TFF1 and/or Ki67 suggesting that cell migration and cell division play important roles in the rapid progression of interval cancers. The observation that TFF1 expression in interval cancers tends to be estrogen-independent and that interval cancers have reduced estrogen receptor expression suggests they may have a reduced response to hormone therapy.