p63/p73 Signaling Axis as a Target for Treatment of Triple-Negative Breast Cancer

缺乏雌激素和孕激素受体表达以及HER 2扩增的乳腺癌， 独特的基因表达谱，表现出不良预后，对常用的化疗药物无反应， 剂.更好地了解这一亚型乳腺癌的分子基础，称为三阴性， 可能导致新的治疗策略的发展。p53家族的转录因子， 包括p53、p63和p73，是乳腺细胞中肿瘤抑制信号通路的关键调节因子。的p53 肿瘤抑制基因在约30%的乳腺癌中发生突变，但在侵袭性乳腺癌中p53突变的发生率更高。 （ER）阴性乳腺癌，并显示与三阴性，“基底样”亚组的强相关性。 尽管p53家族的祖先p63在大多数浸润性乳腺癌中检测不到，但它在乳腺癌中的表达与乳腺癌的发生密切相关。 在约25 - 30%的三阴性基底样肿瘤中表达。表达的p63亚型 （deltaNp 63 α）是一种具有有效转录抑制活性并在上皮细胞存活中起作用的蛋白 和差异化。在一部分三阴性肿瘤中，p63与另一个p53家族协同表达 成员，p73，并且可以拮抗p73转录和肿瘤抑制活性。使用基因 基于表达的化学基因组学方法，我们已经鉴定了一类药物（胰岛素增敏剂）， 调节p73活性以及其他升高p73和降低p63的药物，这是相关的， 这些试剂可以使p63/p73信号传导轴向促凋亡信号传导“倾斜”。在本申请中，我们提出 p63/p73信号传导轴是治疗三阴性肿瘤的强大分子靶点，我们将 确定该轴的调节是否在药物诱导的乳腺肿瘤细胞凋亡中起关键作用。 基于我们实验室和其他实验室的最新发现，我们提出了以下相互关联的假设： 对于同时表达p63和p73的三阴性肿瘤，p63通过抑制p73促进肿瘤细胞存活。 此外，冲击p63/p73信号传导轴的药物的组合使用将具有协同活性。在 其余部分的三阴性肿瘤缺乏p63表达，但表达p73，其他途径是 其被选择用于消除p73促凋亡活性或促进肿瘤细胞存活。提出了三个目标， 测试这些假设。首先，我们将确定肿瘤对新辅助顺铂的反应程度， 紫杉醇和TOR抑制剂依维莫司（RAD 001）与顺铂和紫杉醇治疗的患者 三阴性肿瘤在第二部分中，我们将使用基因表达谱对三阴性癌症进行细分。 并鉴定基因特征，如p63和p73，预测对新辅助化疗的敏感性和反应。 三阴性乳腺癌的治疗。最后，我们将回到临床前研究，分析一组胰岛素 致敏剂单独或与已知的致敏剂组合活化p73和诱导细胞凋亡的能力。 化疗药物在三阴性乳腺癌细胞中的作用，并平行确定 p73活性被激活。 该项目的转化目标和临床影响是为患者确定有效的治疗方法 三阴性乳腺肿瘤

Breast cancers that lack estrogen and progesterone receptor expression as well as HER2 amplification have a distinct gene expression profile, exhibit a poor prognosis and do not respond to commonly used chemotherapeutic agents. A better understanding of the molecular basis of this subset of breast cancers, called triple negative, may lead to the development of new therapeutic strategies against it. The p53 family of transcription factors, including p53, p63 and p73, are key regulators of tumor suppressor signaling pathways in breast cells. The p53 tumor suppressor is mutated in -30% of breast cancer, but incidence of p53 mutation is higher in aggressive (ER)-negative breast cancers and shows strong association with the triple negative, 'basal-like' subgroup. Although the ancestral p53 family member, p63, is not detectable in the majority of invasive breast carcinomas, it is expressed in -25-30% of triple negative, basal-like tumors. The p63 isoforrn that is expressed (deltaNp63alpha) is one that has potent transcriptional repression activity and plays a role in epithelial cell survival and differentiation. In a fraction of triple-negative tumors, p63 is coordinately expressed with another p53 family member, p73, and may be antagonizing p73 transcriptional and tumor suppressive activity. Using a gene expression-based chemical genomics approach we have identified a class of drugs (insulin sensitizers) that modulate p73 activity as well as other drugs that elevate p73 and decrease p63, which is of relevance given that these agents may 'tip' the p63/p73 signaling axis towards pro-apoptotic signaling. In this application, we propose that the p63/p73 signaling axis is a robust molecular target for the treatment triple negative tumors and we will determine if modulation of this axis plays a critical role in drug-induced breast tumor cell apoptosis. Based on recent findings from our laboratory and others we propose the following interrelated hypotheses: In triple negative tumors that express both p63 and p73, p63 promotes tumor cell survival through repression of p73. Further, the combined use of drugs that impinge on the p63/p73 signaling axis will have synergistic activity. In the remaining fraction of triple negative tumors that lack p63 expression, but express p73, other pathways are selected for that abrogate p73 pro-apoptotic activity or promote tumor cell survival. Three aims are proposed to test these hypotheses. In the first, we will determine the degree of tumor response to neoadjuvant cisplatin, paclitaxel, and the TOR inhibitor everolimus (RAD001) versus cisplatin and paclitaxel therapy in patients with triple negative tumors. In the second, we will use gene expression profiling to sub-classify triple negative cancers and identify gene signatures, such as those of p63 and p73, that predict sensitivity and response to neoadjuvant therapy in triple negative breast cancers. Lastly, we will return to preclinical studies to analyze a panel of insulin sensitizers for their ability to activate p73 and induce apoptosis alone or in combination with known chemotherapeutic agents in triple negative breast cancer cells, and in parallel determine the mechanism by which p73 activity is stimulated. The translational goal and clinical impact of this project is the identification of effective therapeutics for patients with triple negative breast tumors