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HER2扩增的乳腺癌 基因表达谱明显不同，预后不良，对常用化疗药物无效 探员们。更好地了解这一乳腺癌亚群的分子基础，称为三阴性， 可能导致针对它的新的治疗策略的发展。P53转录因子家族， 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。P53 在-30%的乳腺癌中，抑癌基因发生突变，但在侵袭性乳腺癌中，P53突变的发生率更高 (ER)阴性的乳腺癌，与三重阴性的“基底样”亚组有很强的相关性。 尽管在大多数浸润性乳腺癌中不能检测到祖先的p53家族成员p63，但它 在-25%-30%的三阴性基底样瘤中表达。表达的p63异构体 (DeltaNp63pha)是一种具有强大的转录抑制活性的基因，在上皮细胞的生存中发挥作用 和差异化。在一小部分三阴性肿瘤中，p63与另一个p53家族协同表达 成员p73，并可能拮抗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确定了一类药物(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，这一点具有相关性 这些药物可能使p63/p73信号轴“倾斜”至促凋亡信号。在此应用程序中，我们建议 P63/p73信号轴是治疗三阴性肿瘤的强有力的分子靶点，我们将 确定这一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。 根据我们实验室和其他实验室最近的发现，我们提出了以下相互关联的假设： 同时表达p63和p73的三重阴性肿瘤，p63通过抑制p73促进肿瘤细胞存活。 此外，联合使用影响p63/p73信号轴的药物将具有协同作用。在 在缺乏p63表达但表达p73的三阴性肿瘤中，剩余的一部分，其他途径是 选择用于消除p73促凋亡活性或促进肿瘤细胞存活。提出了三个目标来 检验这些假设。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抑制剂维罗莫司(RAD001)与顺铂和紫杉醇治疗的比较 三重阴性肿瘤。在第二个实验中，我们将使用基因表达谱对三种阴性癌症进行细分 并确定预测对新佐剂的敏感性和反应的基因特征，如p63和p73 三阴性乳腺癌的治疗。最后，我们将回到临床前研究来分析一组胰岛素 敏感剂能够单独或联合已知的方式激活p73并诱导细胞凋亡 化疗药物在三阴性乳腺癌细胞中的作用，并同时决定了 P73活性受到刺激。 该项目的翻译目标和临床影响是为患者确定有效的治疗方法。 患有三重阴性的乳腺肿瘤

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