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

描述(申请人提供)：在过去的30年里，他莫昔芬()一直是乳腺癌最常用的内分泌治疗药物。在过去的几年中，芳香酶抑制剂被证明在绝经后患者群体中作为辅助治疗优于。此外，芳香酶抑制剂作为耐药性出现后的二线治疗有效，并正在化学预防环境中进行测试。这将在不久的将来带来乳腺癌标准内分泌治疗的范式转变。确定和芳香酶抑制剂耐药的分子机制中的关键因素，无疑将有助于开发合理的治疗靶点。我们在激素依赖的T47D：A18细胞系中建立了耐药的临床前模型，该细胞系被设计为过表达蛋白激酶Cα(PKCA)。来自这些细胞的肿瘤在无瘤小鼠体内以雌激素(E2)非依赖性和耐药的方式生长。基于该模型，我们对临床标本进行了检测，发现在乳腺癌中PKCA的过度表达经常与耐药有关。最近的初步数据表明，T47D：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癌基因，也是乳腺癌干细胞的假定标志。最有趣的是我们的发现，T47D：A18/PKCA耐药的肿瘤在E2或雷洛昔芬(Ral)的存在下会消退。我们的假设是PKCA过表达，对耐药的肿瘤患者可能对RAL、E2或Notch抑制剂的治疗有反应。我们将利用T47D：A18/PKCA乳腺癌模型来研究三种治疗策略：(1)和RAL的对立作用以及RAR和其他SERMS的潜在治疗应用；(2)Notch4的作用和Notch抑制剂在耐药中的作用；(3)雌激素与芳香化酶抑制剂治疗的比较。相关性：对他莫昔芬耐药的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的患者在他莫昔芬治疗期间都会复发，因此需要替代的治疗策略。这项建议将讨论三种潜在的治疗方法，基于蛋白激酶Cα(PKCA)作为生物标记物来指导治疗选择。

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.