SIM2s Regulation of Senescence

描述（由申请人提供）：衰老是乳腺癌进展的主要障碍，由多种应激信号诱导，包括端粒侵蚀、DNA损伤和致癌信号。癌基因诱导的衰老（OIS）已在人类癌症和临床前模型中观察到，并与癌症发生和进展的抑制有关。此外，化疗后的衰老诱导与患者的良好结局相关，也使衰老的激活成为治疗干预的有吸引力的靶点。近年来对乳腺癌的研究表明，诱导上皮间质转化（EMT）可以绕过衰老，促进浸润和转移。然而，我们对衰老旁路的分子遗传学以及乳腺癌进展中衰老和EMT之间平衡的调节的理解存在差距。因此，确定调节EMT和衰老之间转换的机制是重要的，将为乳腺癌进展和治疗提供急需的见解。我们已经表明，Singleminded-2s（SIM 2s;由SIM 2表达），转录因子的bHLH/PAS家族的成员，是一种肿瘤抑制因子，在乳腺上皮细胞中表达，并通过抑制EMT和转移在导管原位癌（DCIS）向浸润性导管癌（IDC）的转变中下调。我们最近的研究结果表明，SIM 2s是乳腺癌衰老的有效诱导剂，并通过与ATM和p53相互作用来实现，并且是CDKN 1A（p21 WAF 1）基因表达所必需的，这是衰老信号传导的关键组成部分。因此，我们假设SIM 2s是一种肿瘤抑制因子，通过调节衰老和EMT之间的平衡来阻断肿瘤形成。为了验证这一假设，我们提出了两个具体目标。在目的1中，我们将确定Sim 2s表达的获得对ErbB 2介导的小鼠乳腺上皮细胞体内转化的影响，以及Sim 2s介导的衰老对p21 Waf 1和p53的需求。在目标2中，我们将定义SIM 2与ATM和p53在DDR通路中的相互作用的物理基础和功能结果，以及乳腺癌细胞衰老的诱导。我们还将研究与SIM 2s介导的CDKN 1A基因表达相关的转录因子募集和染色质改变。我们预计，拟议的研究将更好地定义衰老和EMT之间的联系，并确定SIM 2作为乳腺癌治疗的新靶点。

DESCRIPTION (provided by applicant): Senescence is a major barrier to breast cancer progression and induced by a variety of stress signals including telomere erosion, DNA damage and oncogenic signaling. Oncogene-induced senescence (OIS) has been observed in human cancers and preclinical models, and is associated with inhibition of cancer initiation and progression. Moreover, senescence induction following chemotherapy has been correlated with favorable outcome in patients, also making activation of senescence an attractive target for therapeutic intervention. Recent studies in breast cancer have shown that induction of epithelial mesenchymal transition (EMT) can by-pass senescence and promote invasion and metastasis. However, there are gaps in our understanding the molecular genetics of senescence by-pass and the regulation of the equilibrium between senescence and EMT in breast cancer progression. Therefore, identifying mechanisms that regulate the switch between EMT and senescence is significant and will provide much needed insight into breast cancer progression and treatment. We have shown that Singleminded-2s (SIM2s; expressed from SIM2), a member of the bHLH/PAS family of transcription factors, is a tumor suppressor expressed in breast epithelial cells and down-regulated in transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) by inhibiting EMT and metastasis. Our recent results indicate that SIM2s is a potent inducer of senescence in breast cancer, and does so by interacting with ATM and p53, and is required for CDKN1A (p21WAF1) gene expression, a key component in senescence signaling. We therefore hypothesize that SIM2s is a tumor suppressor that blocks tumor formation by regulating the equilibrium between senescence and EMT. To test this hypothesis we propose two Specific Aims. In Aim 1, we will determine the effect of Sim2s gain of expression on ErbB2-mediated transformation of mouse mammary epithelial cells in vivo and the requirements of p21Waf1 and p53 in Sim2s-mediated senescence. In Aim 2, we will define the physical basis for, and functional outcomes of interactions between SIM2s and, ATM and p53 in the DDR pathway and induction of senescence in breast cancer cells. We will also investigate transcription factor recruitment and chromatin alterations associated with SIM2s-mediated CDKN1A gene expression. We anticipate that the proposed studies will better define the link between senescence and EMT as well as identify SIM2s as a novel target for breast cancer treatment.