Transcriptional Regulation of Dormancy and Emergence in Breast Cancer

乳腺癌在美国女性癌症死亡人数中排名第二。乳腺癌相关疾病 死亡主要是由播散细胞的转移生长引起的。虽然癌细胞的扩散 发生在肿瘤进展的早期，渗出的癌细胞的转移性生长通常需要许多 多年来，由于癌细胞的休眠行为。原则上，乳腺癌患者的存活率应该是 如果通过延长播散性肿瘤细胞的休眠或 减缓进行性转移性生长。我们的首要目标是识别肿瘤细胞固有的 对植物从休眠到出苗的转变和逐步生长至关重要的转录程序 乳腺癌中已确定的转移。在拟议的研究中，我们假设休眠到- 乳腺癌细胞的出现、转换和进行性转移生长需要Myocardin的作用。 相关转录因子(MRTF)，血清反应因子(SRF)的转录共激活因子。为了测试这一点 假设，我们提出了两个具体的目标。在目标1中，我们将进行遗传和药理学证明- 建立MRTF/SRF转录轴在休眠调节中的作用的概念研究 乳腺癌细胞的转移性生长。Aim 2将测试MRTF/SRF活性是否促进转移 乳腺癌细胞的生长通过肿瘤内在和外在两种机制。建议进行的研究 将采用高度全面的实验策略，将可诱导的功能中断和 药物干预策略，转移部位肿瘤细胞活性的活体成像， 肺、肝肿瘤微环境器官模型研究肿瘤休眠，小鼠模型 研究，使用患者衍生的有机类化合物和BC的临床样本，以及多重定量IHC。一个 这些研究的成功完成将使MRTF成为一种新的休眠-涌现调节因子 乳腺癌细胞行为的机制细节，并为药理学提供概念验证 介入MRTF作为一种诱导乳腺癌休眠和抑制转移生长的新策略。

Breast cancer ranks second among cancer deaths in women in the United States. Breast cancer-related mortality primarily results from metastatic growth of disseminated cells. While dissemination of cancer cells occurs early during tumor progression, metastatic outgrowth of extravasated cancer cells often takes many years due to the dormant behavior of cancer cells. In principle, the survival of breast cancer patients should be improved if metastatic burden is reduced by either prolonging the dormancy of disseminated tumor cells or slowing down progressive metastatic growth. Our overarching goal is to identify tumor cell-intrinsic transcriptional programs that are critical for dormancy-to-emergence transition and progressive growth of established metastases in breast cancer. In the proposed study, we hypothesize that dormancy-to- emergence switch and progressive metastatic growth of breast cancer cells require the action of Myocardin- related transcription factor (MRTF), a transcriptional coactivator of serum-response factor (SRF). To test this hypothesis, we propose two specific aims. In Aim 1, we will conduct genetic and pharmacological proof-of- concept studies to establish the role of MRTF/SRF transcriptional axis in regulation of dormancy and metastatic growth of breast cancer cells. Aim 2 will test whether MRTF/SRF activity promotes metastatic growth of breast cancer cells through both tumor-intrinsic and –extrinsic mechanisms. The proposed studies will employ a highly comprehensive experimental strategy integrating inducible functional disruption and pharmacological intervention strategies, intravital imaging of tumor cell activity at metastatic sites, organotypic models of lung and liver tumor microenvironment to study tumor dormancy, mouse model studies, use of patient-derived organoids and clinical samples of BC, and multiplexed quantitative IHC. A successful completion of these studies will establish MRTF as a novel regulator of dormancy-emergence behavior of breast cancer cells with mechanistic details, and provide proof-of-concepts for pharmacological intervention of MRTF as a novel strategy to induce dormancy and curb metastatic growth in breast cancer.