T_1G_3膀胱尿路上皮癌复发与进展影响因素分析

目的探讨影响T1G3膀胱尿路上皮癌复发与进展的因素,为临床治疗提供循证医学依据。方法回顾性分析1997年至2009年我科治疗的62例行经尿道膀胱肿瘤电切术（TURBT）＋膀胱灌注治疗的T1G3膀胱尿路上皮癌患者,对这些患者进行随访并对生存预后进行分析。生存函数运用Kaplan-Meier法,单因素和多因素分析运用Cox回归,并采用Log-rank法行显著性检验。结果中位随访期40个月（6～140个月）,41例（66.0%）复发,2、5年无复发生存率分别为43.4%、35.1%。14例（23.0%）出现进展,2、5年无进展生存率分别为86.4%、83.5%。将与复发相关的危险因素纳入Cox回归多因素生存分析后提示肿瘤复发的危险因素为肿瘤数目（RR=2.250）、肿瘤大小（RR=1.039）、既往复发情况（RR=2.162）,P均〈0.05;与进展相关的危险因素纳入Cox回归多因素生存分析,提示肿瘤进展的危险因素为肿瘤数目（RR=3.695）。结论肿瘤数目是T1G3膀胱尿路上皮癌复发最大的影响因素,其次为既往复发情况和肿瘤大小,肿瘤数目是肿瘤进展的相关因素;T1G3膀胱尿路上皮癌需结合肿瘤数目、肿瘤大小、既往复发情况综合考虑治疗方案。     

上尿路尿路上皮肿瘤术后无瘤生存期的影响因素

目的探讨上尿路尿路上皮肿瘤(UTUC)患者根治术后无瘤生存期的影响因素。方法 85例UTUC患者,均接受根治性肾输尿管切除+输尿管膀胱开口袖套状切除术治疗,术后部分患者给予规范化膀胱药物灌注化疗。术后进行跟踪随访,统计85例患者无瘤生存期及3年无瘤生存率,分析无瘤生存的影响因素。结果 85例患者随访36~66个月,中位随访时间52.6个月,无瘤生存时间19~63个月,中位无瘤生存时间38.5个月,3年无瘤生存率为54.12%。多因素分析显示高龄、吸烟史、多发性灶、TNM分期均为影响UTUC患者根治术后无瘤生存的独立危险因素(P0.05),术后膀胱灌注化疗是根治术后无瘤生存的保护因素(P0.05)。结论高龄、吸烟史、多发性灶、高TNM分期均不利于延长UTUC患者根治术后无瘤生存期,而术后膀胱灌注化疗有助于提高无瘤生存率,临床应高度重视。     

凋亡抑制蛋白Livin在上尿路移行细胞癌中的表达及其与预后的关系

目的检测Livin蛋白在人正常膀胱组织及上尿路移行细胞癌组织中的表达情况,并分析其表达与肿瘤临床分期、病理分级及肿瘤复发之间的关系。方法采用免疫组织化学法检测12例正常上尿路上皮组织切片及58例上尿路移行细胞癌组织标本及中Livin基因的表达情况。结果 Livin蛋白在正常上尿路上皮组织中无表达,而在移行细胞癌组织中高表达,阳性表达率为60.3%。Livin蛋白在不同性别、年龄及是否伴有淋巴结转移患者中的表达差异无统计学意义(P>0.05),而不同分期及分级的组间表达差异具有统计学意义(P<0.05)。随访9-45个月(平均29.3个月),肿瘤患者中共有27例出现局部或膀胱复发,总复发率为46.6%,其中Livin表达阴性组3年估计无瘤复发生存率为49.5%,而Livin表达阳性患者3年估计无瘤复发生存率为30.1%,二者之间差异显著(P=0.04)。结论 Livin在正常上尿路移行上皮组织中不表达,在上尿路移行细胞癌组织中高表达,Livin的表达与上尿路移行细胞癌分期、分级密切相关,与肿瘤复发密切相关。     

非浸润性膀胱尿路上皮肿瘤中Ki-67、c-erbB-2的表达及意义

目的 探讨非浸润性膀胱尿路上皮肿瘤的组织学形态及Ki-67、c-erbB-2表达的意义.方法 依据WHO(2004)泌尿系统肿瘤中ISUP分类标准进行组织学观察及分类.应用免疫组化方法检测70例膀胱尿路上皮肿瘤标本中Ki-67、c-erbB-2的表达水平,并对其进行3～60个月随访.结果 在尿路上皮乳头状瘤(UP)、乳头状肿瘤低恶性潜能(PUNLMP)、低级别乳头状尿路细胞癌(LGPUC)和高级别乳头状尿路细胞癌(HGPUC)中,Ki-67(L)分别为4.05±2.3、13.8±6.9、30.1±4.4和59.5±6.8;c-erbB-2与组织学分级有关(P<0.01).UP患者随访无复发;PUNLMP复发率为15%(3/20),LGPUC复发率为65%(13/20),HGPUC复发率为70%(7/10).结论 Ki-67和c-erbB-2可作为膀胱尿路上皮肿瘤细胞增殖程度及组织学诊断的参考指标.     

Caveolin-1在膀胱尿路上皮癌的表达及其与复发的关系

目的:探讨窖蛋白-1(Caveolin-1)在膀胱尿路上皮癌、正常膀胱黏膜中表达,旨在探讨其与膀胱尿路上皮癌病理分级、临床分期、数目及复发等生物学特性的关系。方法:应用免疫组化法检测Caveolin-1在85例膀胱尿路上皮癌,20例正常膀胱组织中表达情况。结果:(1)Caveolin-1在膀胱尿路上皮癌和正常膀胱黏膜中的表达率分别为40%、0%,两者之间差异有统计学意义(P<0.005)。(2)Caveolin-1在Ⅰ级、Ⅱ级、Ⅲ级膀胱尿路上皮癌组织中的阳性率分别为9.5%、35.9%、72.0%,三者之间差异具有统计学意义(P<0.005)。(3)Caveolin-1在浅表性膀胱癌(Tis～T1)和浸润性膀胱癌(T2～T4)中的表达率分别为16.7%、57.1%,两者之间差异有统计学意义(P<0.005)。(4)Caveolin-1在单发性和多发性膀胱尿路上皮癌组织上的表达分别为35.9%、46.9%,两者之间差异无统计学意义(P﹥0.05)。(5)Caveolin-1在初发性和复发性膀胱尿路上皮癌组织中的表达率分别为32.8%、61.9%,两者之间差异有统计学意义(P<0.05)。结论:(1)Caveolin-1可以作为一种膀胱癌标记物来评估膀胱癌的恶性度,对膀胱癌的病理分级及临床分期提供指导。(2)Caveolin-1阳性表达可能是膀胱癌复发的高危因素。     

Her-2/Neu在胃癌组织中的表达及其临床意义

目的检测Her-2/Neu在不同胃癌组织中的表达,分析Her-2/Neu的表达与临床病理特征的相关性及其对预后的影响。方法应用免疫组化二步法,检测60例胃癌患者术后标本中Her-2/Neu的表达情况,并结合临床病理特征及该60例患者的随访资料进行综合分析,具体为:采用χ2分析Her-2/Neu在不同组织类型胃癌中的表达是否有差异;采用Spearman进行等级相关分析,分析Her-2/Neu表达与临床病理特征的相关性,采用Kaplan-Meier法进行生存期分析,分析Her-2/Neu表达对胃癌术后患者无病生存期及总生存期的影响。结果 (1)在60例胃癌组织中Her-2/Neu表达阳性者为29例(48.3%),在不同组织类型的胃癌中表达无差异。(2)Her-2/Neu的表达与浸润深度、淋巴结转移、临床分期有关,Spearman相关系数分别为0.360、0.321、0.412(P均<0.05)。Her-2/Neu表达阳性的患者无病生存期及中位生存期均显著低于表达阴性者。结论 (1)Her-2/Neu的表达与肿瘤浸润深度、淋巴结转移情况及TNM分期相关。(2)生存分析显示,Her-2/Neu阳性表达者生存期劣于阴性表达者。     

多器官尿路上皮癌误诊分析并文献复习

目的探讨多器官尿路上皮癌的误诊原因及预防措施。 方法回顾分析2006年2月至2012年10月收治被误诊误治的3例多器官尿路上皮癌患者临床资料。 结果3例均为男性,年龄分别为83岁、69岁和71岁,均以血尿待查住院。例1、例2首次均以膀胱移行细胞癌在外院多次行经尿道膀胱肿瘤切除术(TURBt),例1于3个月前,曾在外院先后行腹腔镜下膀胱癌根治术和肾切除术、回肠膀胱术;例2在入院前,曾在外院行肾输尿管部分切除;例3以肾盂癌在外院行肾、输尿管部分切除术。患者入院后行尿细胞学检查和B超、静脉肾盂造影(IVP)、CT尿路造影(CTU)或磁共振(MRI)检查及膀胱镜检查。例1诊断为复发性膀胱癌术后,肾切除术后右输尿管残段癌,左肾积水,肾功能不全,全身多发性转移;例2为复发性膀胱肿瘤电切术后,右输尿管下端癌,多脏器转移,多器官衰竭;例3为右肾盂癌肾切除输尿管部分切除术后,膀胱癌。例1给双"J"管置入内引流术,例2给予营养支持、对症处理,例3行膀胱部分加输尿管残段切除术,BCG膀胱灌注局部化疗。全组患者随访6年,例1、例2分别于术后8个月和3个月死于肿瘤全身转移、多脏器衰竭,例3无瘤生存6年健在。 结论提高对多器官尿路上皮癌的认识,不能满足于单一器官肿瘤的诊断,不但要给予CT、MRI等检查,还需行尿脱落细胞学检查,必须行膀胱镜检查,尤其是复发性膀胱癌应警惕上尿路上皮癌同时存在的可能,正确的术式选择是延长患者生存期的关键。     

尿路上皮癌特异新基因尿路上皮癌抗原1表达强度与尿路上皮癌分级相关性研究

目的 找到与尿路上皮癌抗原1(UCA1)表达强度相关的临床病理学参数,为该基因在膀胱癌发生或进展中的功能学研究提供依据.方法 用逆转录PCR检测83例尿路上皮癌(膀胱癌48例,肾盂癌23例,输尿管癌12例)组织中UCA1的表达强度,同时用Northern印迹法分别检测3例尿路上皮癌(3种癌各1例)的UCA1表达.用Spearman′s非参数分析研究UCA1表达强度与4个临床病理学参数(患者性别,肿瘤分期、分级及数量)的相关性.按照4个临床病理学参数将尿路上皮癌分为不同亚组,用Mann-Whitney检验来比较UCA1在不同亚组中的表达差异.结果 UCA1在83例尿路上皮癌中总体表达率达84.3%(70/83),在3种尿路上皮癌中的表达率分别为85.4%(41/48)、83.3%(10/12)、82.6%(19/23).UCA1表达强度与肿瘤分级有相关性,相关系数0.269(P=0.014),且高级别肿瘤的表达强度明显高于低级别肿瘤,差异有统计学意义(P=0.019),而患者性别、分期及肿瘤数量与UCA1表达强度均无相关性.结论 UCA1与尿路上皮癌分级的显著相关性说明该基因可能与尿路上皮癌的进展有关,对此需要更深入的功能学研究加以证实.     

ErbB3在肿瘤生物学活性和肿瘤治疗方面的作用

ErbB3是表皮生长因子受体家族的第3个成员,是1989年由Kraus首先发现,其生物学活性类似该家族中的其他成员,具有酪氨酸蛋白激酶活性,其酪氨酸激酶活性区域高度保守.最近的研究发现ErbB3在肿瘤的发生与发展中起着非常重要的作用.1 ErbB3的结构与肿瘤的关系ErbB家族的所有成员都只有一个糖基化位点是保守的.这表明糖基化位点可能与ErbB家族各个成员的独特功能有关[1].其中糖基化位点Asn[2](天冬酰胺)对调节ErbB3的功能非常重要.例如在CHO细胞中,如果这个糖基化位点突变为谷氨酰胺,将导致缺少配体的ErbB2与ErbB3形成异源二聚体,增加细胞癌变的可能性.ErbB3的胞外配体结构域由四个子域组成,即Ⅰ(L1),Ⅱ(C1),Ⅲ (L2)和Ⅳ (C2).在缺少配体时,通过分子内Ⅱ区和Ⅳ区的相互作用(包括Ⅱ区中一个β环),使ErbB3处于闭合状态,从而阻止Ⅰ区和Ⅲ区相互作用.     

膀胱尿路上皮癌组织中Livin和血管内皮生长因子蛋白的表达及其相关性研究

目的 探讨膀胱尿路上皮癌组织中凋亡抑制因子Livin和血管内皮生长因子(VEGF)蛋白的表达与临床病理参数的关系及其相关性.方法 采用免疫组织化学S-P法检测69例膀胱尿路上皮癌和10例正常膀胱黏膜组织中Livin和VEGF蛋白的表达状况,结合临床病理学资料进行统计学分析.结果 Livin和VEGF蛋白在膀胱尿路上皮癌组织的阳性表达率分别为65.2%(45/69)和46.4%(32/69),而正常膀胱黏膜组织中均不表达(均为0.0%),组间比较差异有统计学意义(P均＜0.01).在有、无复发组的膀胱尿路上皮癌组织中Livin蛋白的阳性表达率差异有统计学意义[有复发78.8%(26/33),无复发48.1%(13/27),χ2=6.13,P＜0.05],而在不同病理分级组、不同临床分期组及肿瘤单、多发组的膀胱尿路上皮癌组织中Livin蛋白的阳性表达率差异均无统计学意义(G1 55.6%,G2 64.3%,G3 73.9%;Ta～T1 61.9%,T2～T4 70.4%;单发59.6%,多发77.3%;χ2值分别为1.52、0.52、2.07,P均＞0.05).在不同病理分级组和不同临床分期组的膀胱尿路上皮癌组织中VEGF蛋白的阳性表达率差异均有统计学意义(G116.7%,G2 53.6%,G3 60.9%;Ta～T1 33.3%,T2～T4 66.7%;χ2值分别为8.91、7.34,P＜0.05或P＜0.01),而在肿瘤单、多发组和有、无复发组的膀胱尿路上皮癌组织中VEGF蛋白的阳性表达率差异均无统计学意义(单发46.8%,多发45.5%;有复发51.5%,无复发40.7%,χ2值分别为0.01、0.69,P均＞0.05).膀胱尿路上皮癌组织中Livin与VEGF蛋白的表达无相关关系(r=0.056,P＞0.05).结论 Livin和VEGF蛋白的高表达可能在膀胱尿路上皮癌的发生过程中起重要作用.联合检测二者的变化有望成为膀胱尿路上皮癌诊断和判断预后的一项客观指标.

Abstract：

Objective To investigate the expressions of Livin protein and VEGF protein in bladder urothelial carcinoma(BUC) ,and theirs relationships with the clinicopathologic parameters of bladder urothelial carcinoma. Methods The expression of Livin and VEGF protein in 69 samples of BUC tissue and 10 samples of normal bladder epithelium tissue were detected by immunohistochemical SP method. Their relationships with clinicopathologic data were statistically analyzed. Results The positive expression rate of Livin and VEGF in BUC tissues were 65.2% (45/69) and 46.4% ( 32/69), but negative in normal bladder epithelium tissues, which showed significant differences in the comparison (Ps ＜ 0. 05 ). We found significant difference in the comparison of Livin positive rate between groups with or without recurrence ( 78. 8 % vs 48. 1%, χ2 = 6. 13, P ＜ 0. 05 ); but no differences in pathological grade,TNM stage and tumor number( Gl 55.6% ,G2 64. 3% ,G3 73.9% ;Ta ～ T1 61.9% ,T2 ～ T4 70. 4%; Single-tumor 59. 6%, multi-tumor 77.3%; χ2 = 1.52,0. 52,2.07, Ps ＞ 0. 05 ). For BUC,the expression of VEGF was correlated with the pathological grade,TNM stage( Gl 16. 7% ,G2 53.6% ,G3 60. 9%, χ2 = 8. 91; Ta ～ T1 33.3%, T2 ～ T4 66. 7%; χ2 = 7. 34; Ps ＜ 0. 05 ), but not the tumor number and recurrence( Single-tumor 57.4% , multi-tumor 59. 1%, χ2 = 0. 01; with recurrence 51.5% , without recurrence 40. 7% ,χ2= 0. 69; Ps ＞ 0. 05 ). We found no relationship between the expression of Livin and VEGF (r =0. 056,P ＞ 0. 05 ). Conclusion The overexpressions of Livin and VEGF protein may play an important role in the occurrence and development of BUC. Combind detection of these two protein can be used in the diagnosis and prognosis of BUC.     

不同宫颈组织中erbB3、erbB4表达及作用

目的　探讨不同宫颈组织中 erb B3、erb B4表达及其意义。方法　应用免疫组化 HIGH- SABC方法检测了5 0例宫颈鳞癌组织 ,15例中度不典型增生 ,15例正常宫颈上皮组织进行 erb B3、erb B4的表达。结果　在不同宫颈组织中 ,erb B3、erb B4的阳性表达率依次为宫颈鳞癌 >中度不典型增生 >正常宫颈组织 ;erb B3、erb B4表达与宫颈癌细胞的分化程度呈负相关 ,与 FIGO分期呈正相关 ,与其他临床病理参数不相关。结论　 erb B3和 erb B4在宫颈癌的发生发展中可能起着重要的作用 ,它们可以预测宫颈癌恶化潜能 ,但不能作为宫颈癌预后的独立评价指标。     

Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3

The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse.     

Oligoclonal antibodies to target the ErbB family

Introduction: Use of mAbs to inhibit signaling through the ErbB receptor tyrosine kinase family has proven to be an effective strategy for treating ErbB-driven cancers. Advances in the field of antibody engineering and manufacturing now allow us to more effectively mimic the natural immune response by generating oligoclonal mixtures of antibodies against desired targets of interest.

Areas covered: In this review, we examine the literature describing the development of oligoclonal mixtures of antibodies against ErbB family members and the impact of those mixtures on preclinical and clinical efficacy.

Expert opinion: Oligoclonal antibodies, facilitated by the improved antibody engineering and manufacturing techniques, hold the promise of improving patient outcomes. Through the use of empirical methods, oligoclonal mixtures with enhanced capacity to block signaling through ErbB family members can be identified. The intrinsic mechanisms associated with each of the component mAbs provide an opportunity to block signaling via multiple mechanisms of action. In addition, combinations of antibodies targeting multiple ErbB family members provide the capacity to down-regulate signaling through multiple components of this critical pathway.     

Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors

ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously shown. Here, we show that expression of a 95-kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2(+) breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2(+) breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated C-terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib-sensitive ErbB2(+) breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear, truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation may enhance the clinical efficacy of ErbB2 TKIs.     

ErbB2 Induces Notch1 Activity and Function in Breast Cancer Cells

The ErbB2 (Her2/neu epidermal growth receptor family) oncogene is overexpressed in 30% to 40% of human breast cancers. Cyclin D1 is the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) tumor suppressor and is an essential downstream target of ErbB2‐induced tumor growth. Herein, we demonstrate that ErbB2 induces the activity of the Notch signaling pathway. ErbB2 induction of DNA synthesis, contact‐independent growth, and mammosphere induction required Notch1. ErbB2‐induced cyclin D1 and cyclin D1 expression was suficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using foxed Notch (Notch^fl/fl) mice demonstrated that cyclin D1 is induced by Notch1. Genetic deletion of cyclin D1 or small interfering RNA (siRNA) to cyclin D1‐reduced Notch1 activity and reintroduction of cyclin D1 into cyclin D1‐deficient cells restored Notch1 activity through the inhibition of Numb, an endogenous inhibitor of Notch1 activity. Thus, cyclin D1 functions downstream as a genetic target of Notch1, amplifies Notch1 activity by repressing Numb, and identifies a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.     

ErbB receptors: from oncogenes to targeted cancer therapies

Understanding the genetic origin of cancer at the molecular level has facilitated the development of novel targeted therapies. Aberrant activation of the ErbB family of receptors is implicated in many human cancers and is already the target of several anticancer therapeutics. The use of mAbs specific for the extracellular domain of ErbB receptors was the first implementation of rational targeted therapy. The cytoplasmic tyrosine kinase domain is also a preferred target for small compounds that inhibit the kinase activity of these receptors. However, current therapy has not yet been optimized, allowing for opportunities for optimization of the next generation of targeted therapy, particularly with regards to inhibiting heteromeric ErbB family receptor complexes.     

ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

Aberrant regulation of the erythroblastosis oncogene B (ErbB) family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers. ErbB3 is required in luminal mammary epithelial cells (MECs) for growth and survival. Since breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and more frequent ERBB3 gene copy gains in luminal A/B breast cancers compared with other breast cancer subtypes. In cell culture, ErbB3 increased growth of luminal breast cancer cells. Targeted depletion of ErbB3 with an anti-ErbB3 antibody decreased 3D colony growth, increased apoptosis, and decreased tumor growth in vivo. Treatment of clinical breast tumors with the antiendocrine drug fulvestrant resulted in increased ErbB3 expression and PI3K/mTOR signaling. Depletion of ErbB3 in fulvestrant-treated tumor cells reduced PI3K/mTOR signaling, thus decreasing tumor cell survival and tumor growth. Fulvestrant treatment increased phosphorylation of all ErbB family RTKs; however, phospho-RTK upregulation was not seen in tumors treated with both fulvestrant and anti-ErbB3. These data indicate that upregulation of ErbB3 in luminal breast cancer cells promotes growth, survival, and resistance to fulvestrant, thus suggesting ErbB3 as a target for breast cancer treatment.