PKC Alpha as a Marker for Logical Therapeutic Approaches to Breast Cancer

描述（由申请人提供）：在过去的30年里，他莫昔芬（TAM）一直是乳腺癌最常用的内分泌治疗药物。在过去的几年中，已证明芳香酶抑制剂作为绝经后患者人群的辅助治疗上级于TAM。此外，芳香酶抑制剂作为TAM耐药性出现后的二线治疗是有效的，并且正在化学预防环境中进行测试。这将在不久的将来为乳腺癌的标准内分泌治疗带来范式转变。识别的关键因素参与耐药的分子机制，TAM和芳香化酶抑制剂无疑将导致逻辑治疗目标的发展。我们已经开发并表征了TAM抗性的临床前模型，该模型在经工程改造以过表达蛋白激酶C α（PKCa）的依赖于紫杉醇的T47 D：A18细胞系中。来源于这些细胞的肿瘤在无胸腺小鼠中以雌激素（E2）非依赖性和TAM抗性的方式生长。基于这个模型，我们检查了临床标本，发现PKCa的过度表达经常与人类乳腺癌中的TAM耐药相关。最近的初步数据表明，T47 D：A18/PKCa细胞和肿瘤表达高水平的Notch-4，这是一种已知的乳腺癌基因和乳腺癌干细胞的推定标志物。最有趣的是，我们发现T47 D：A18/PKCa TAM耐药肿瘤在E2或雷洛昔芬（RAL）存在下消退。我们的假设是，患者中PKC α过表达、TAM耐药的肿瘤可能对RAL、E2或Notch抑制剂治疗有反应。T47 D：A18/PKCa乳腺癌肿瘤模型将用于研究三种治疗性治疗策略：（1）TAM和RAL的相反作用以及RAL和其他SERMS的潜在治疗应用，（2）Notch 4的作用和Notch抑制剂在TAM抗性中的作用;以及（3）与芳香酶抑制剂治疗相比雌激素的功效。相关性：他莫昔芬耐药乳腺癌的出现是晚期疾病管理中的一个关键问题。由于基本上所有转移性疾病患者在他莫昔芬治疗期间都会复发，因此需要替代治疗策略。该提案将基于蛋白激酶C α（PKCa）作为生物标志物来指导治疗选择，以解决三种潜在的治疗方法。

DESCRIPTION (provided by applicant): For the past 30 years, tamoxifen (TAM) has been the most often prescribed endocrine treatment for breast cancer. In the past few years it was demonstrated that aromatase inhibitors are superior to TAM as adjuvant therapy in the postmenopausal patient population. Furthermore, aromatase inhibitors are effective as a second-line treatment following the emergence of TAM resistance and are being tested in the chemoprevention setting. This will bring a paradigm shift in the standard endocrine therapy for breast cancer in the near future. Identification of the key factors involved in the molecular mechanism of resistance to both TAM and aromatase inhibitors will undoubtedly lead to the development of logical therapeutic targets. We have developed and characterized a preclinical model of TAM resistance in the hormone-dependent T47D:A18 cell line that was engineered to overexpress protein kinase C alpha (PKCa). Tumors derived from these cells grow in athymic mice in an estrogen (E2)-independent and TAM-resistant fashion. Based on this model we examined clinical specimens and discovered that overexpression of PKCa is frequently associated with TAM resistance in human breast cancers. More recent preliminary data indicate that the T47D:A18/PKCa cells and tumors express high levels of Notch-4, a known breast oncogene and putative marker of breast cancer stem cells. Most interesting is our finding that T47D:A18/PKCa TAM-resistant tumors regress in the presence of E2 or raloxifene (RAL). It is our hypothesis that PKCa overexpressing, TAM-resistant tumors in patients may respond to treatment with RAL, E2 or Notch inhibitors. The T47D:A18/PKCa breast cancer tumor model will be used to investigate three therapeutic treatment strategies: (1) the opposing actions of TAM and RAL and the potential therapeutic application of RAL and other SERMS, (2) the role of Notch4 and effect of Notch inhibitors in TAM-resistance; and (3) the efficacy of estrogen as compared to aromatase inhibitor therapy. Relevance: The emergence of tamoxifen-resistant breast cancer is a critical problem in the management of advanced disease. Since essentially all patients with metastatic disease will relapse during tamoxifen treatment, alternative therapeutic strategies are needed. This proposal will address three potential approaches to treatment based on protein kinase C alpha (PKCa) as a biomarker to guide therapeutic choice.