Targeted Chemoprevention of Breast Cancer: From the Bench to Clinical Testing

描述（由申请人提供）：目前，靶向药物用于治疗ER-乳腺癌的临床试验，但尚未进行充分的预防试验。这是因为，如果没有更好地了解人类乳腺癌起始的生物学，用于预防ER-乳腺癌的靶向药物的I/II期测试将过于冒险和昂贵。为了应对这些挑战，我们的目标是在我们的高风险队列中确定在ER-乳腺癌开始时激活的关键信号网络，并使用这些网络来靶向预防。正常的乳腺稳态需要信号网络的协调调节。目前我们还不清楚1)在侵袭性ER-乳腺癌中激活的信号网络是否也在乳腺异型性中被激活，2)如果是，特定信号网络的激活是否能预测癌症的发生和进展。在这里，我们将研究异型性中的信号网络激活是否能预测随后的癌症病因。Akt/mTOR、IL6/Stat3、EGRF/MEK/ERK和线粒体存活途径的激活可以预测ER-乳腺癌的侵袭性生物学。我们的初步数据提供了证据，表明这些不良预后信号网络的激活可以在高危女性的乳腺异型中检测到。然而，仅仅因为我们可以识别受试者之间具有高类别间变异系数的特征，并不一定意味着这些过程对癌症病因学很重要。本研究将验证以下假设：在高危女性的乳腺异型性中可以检测到雌激素受体乳腺癌侵袭性行为背后的信号通路，以及这些信号通路是否可以用于预测癌症的发生和指导有针对性的预防策略。目的1将测试在ER-乳腺癌中发现的磷酸化蛋白特征是否存在于高危女性的癌前病变中。目的2将前瞻性地研究磷酸化蛋白特征是否能预测ER-乳腺癌的发生。目的3将研究RPPM特征是否能预测体外对靶向药物的敏感性。Aim 4将进行试点测试，并使用磷蛋白特征来选择和跟踪对靶向药物的反应，以预防患有乳腺异型性的高风险女性的乳腺癌。意义：在这里，我们将确定在乳腺癌起始过程中被激活的蛋白质信号通路。在本提案中获得的信息将使我们能够识别非典型性中激活的信号通路，测试通路激活是否预测癌症病因，并使用该信息来选择和跟踪对靶向药物的反应。

DESCRIPTION (provided by applicant): Currently, targeted agents are in clinical testing for treatment of ER- breast cancer, but have not been adequately tested for prevention. This is because, without a better understanding of the biology of human breast cancer initiation, Phase I/II testing of targeted agents for preventing ER- breast cancer will be too risky and expensive. To meet these challenges, we aim to identify key signaling networks activated during initiation of ER- breast cancer in women in our high-risk cohort and use these networks to target prevention. Normal mammary gland homeostasis requires the coordinated regulation of signaling networks. Currently we lack an understanding of 1) whether the signaling networks that are activated in aggressive ER- breast cancer are also activated in mammary atypia, and 2) if so, whether activation of specific signaling networks predicts cancer initiation and progression. Here we will investigate whether signaling network activation in atypia predicts subsequent cancer etiology. Activation of Akt/mTOR, IL6/Stat3, EGRF/MEK/ERK, and mitochondrial survival pathways are known to predict aggressive biology in ER- breast cancer. Our Preliminary Data provide evidence that activation of these poor-prognosis signaling networks can be detected in mammary atypia from high risk women. However, just because we can identify signatures with high inter-class coefficients of variation between subjects, does not necessarily imply those processes are important for cancer etiology. Here will test the hypothesis that signaling pathways that underlie the aggressive behavior of ER- breast cancer can be detected in mammary atypia from high-risk women, and whether these signaling pathways can be used to predict cancer initiation and guide targeted prevention strategies. Aim 1 will test whether phosphoprotein signatures identified in ER- breast cancers are present in premalignant lesions in high-high risk women. Aim 2 will prospectively investigate whether phosphoprotein signatures predict initiation of ER- breast cancer. Aim 3 will investigate whether RPPM signatures predict in vitro sensitivity to targeted agents. Aim 4 will perform Pilot Testing and use phosphoprotein signatures to select and track response to targeted agents to prevent breast cancer in high-risk women with mammary atypia. Significance: Here we will identify protein signaling pathways that are activated during breast cancer initiation. Information gained in this proposal will allow us to identify activated signaling pathways in atypia, test whether pathway activation predicts cancer etiology, and use this information to select, and track response to, targeted agents.