SIM2s Regulation of Senescence

描述(申请人提供)：衰老是乳腺癌进展的主要障碍，由多种应激信号引起，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，并与抑制肿瘤的发生和发展有关。此外，化疗后的衰老诱导与患者的良好结果相关，也使激活衰老成为治疗干预的一个有吸引力的靶点。最近在乳腺癌中的研究表明，诱导上皮间充质转化(EMT)可以绕过衰老，促进侵袭和转移。然而，在乳腺癌进展过程中衰老旁路的分子遗传学和衰老与EMT之间的平衡调节方面，我们还存在着一些空白。因此，识别调节EMT和衰老之间切换的机制具有重要意义，并将为乳腺癌的进展和治疗提供亟需的洞察。我们发现SIM2s(SIM2s；来源于SIM2)是转录因子bHLH/PAS家族的成员之一，是一种在乳腺上皮细胞中表达的肿瘤抑制因子，并通过抑制EMT和转移而下调从导管原位癌(DCIS)到浸润性导管癌(IDC)的过程。我们最近的研究结果表明，SIM2S是乳腺癌衰老的有效诱导者，它与ATM和P53相互作用，并且是衰老信号的关键成分CDKN1A(P21WAF1)基因表达所必需的。因此，我们假设SIM2s是一种肿瘤抑制因子，通过调节衰老和EMT之间的平衡来阻止肿瘤的形成。为了检验这一假设，我们提出了两个具体目标。在目的1中，我们将确定Sim2s的表达增加对ErbB2介导的小鼠乳腺上皮细胞体内转化的影响以及在Sim2s介导的衰老过程中对p21Waf1和p53的需求。在目标2中，我们将确定SIM2与DDR通路中的ATM和P53相互作用以及诱导乳腺癌细胞衰老的物理基础和功能结果。我们还将研究与SIM2s介导的CDKN1A基因表达相关的转录因子招募和染色质变化。我们预计，拟议的研究将更好地确定衰老和EMT之间的联系，并确定SIM2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.