Complex Role of HSF1 in Breast Cancer

描述(申请人提供)：HSF1是热休克蛋白合成的关键转录调节因子，它定义了对高温的反应，并影响对某些常规药物和辐射的抗药性。最近，基于模型和人群研究，HSF1已成为乳腺癌发生的主要因素。我们已经证明，HSF1通过控制癌基因诱导的衰老和肿瘤血管生成，在癌细胞的恶性转化和维持中发挥重要作用。为了促进我们对肿瘤发生和辐射抵抗的理解，并在特定的癌症类型中合理地靶向HSF1，我们将解决以下基本问题：(1)在Her2阳性的癌症中HSF1激活的关键机制是什么，(2)HSF1如何影响Her2阳性乳腺癌的发生和发展，以及(3)HSF1在抵抗电离辐射中的作用是什么。目标1将阐述HSF1如何在乳腺肿瘤发生中受到调控。我们将通过选择热休克反应中观察到的信号转导途径，或者作为传统的HER2介导的癌症信号的一部分，来阐明HSF1在肿瘤中是由于非整倍体相关的蛋白毒性而被结构性激活的。在目标2中，我们将阐明HSF1如何进入功能复合体以响应Her2，并影响全球转录。然后，我们将阐明HSF1介导的转录在癌细胞中的作用，确立HSF1是一种癌症干细胞因子，是上皮/间充质转化的参与者，也是肿瘤转移的决定因素(目标3)。最后，我们将通过测试辐射抵抗与HSF1相关的假设来确定HSF1如何决定癌症对电离辐射的反应 肿瘤干细胞的介导性控制。

DESCRIPTION (provided by applicant): HSF1 is the key transcriptional regulator of heat shock protein synthesis that defines the response to hyperthermia, and affects resistance to certain conventional drugs and radiation. Recently, based on both model and population studies, Hsf1 has emerged as a major factor in breast cancer development. We have demonstrated that HSF1 plays an essential role in malignant transformation and maintenance of cancer cells by controlling oncogene-induced senescence, and tumor angiogenesis. To advance our understanding of oncogenesis and radiation resistance, and to rationally target Hsf1 in specific cancer types, here we will address fundamental questions: (1) what are the key mechanisms of Hsf1 activation in Her2-positive cancer, (2) how does Hsf1 affect development and progression of Her2-positive breast cancer, and (3) what is the role of HSF1 in resistance to ionizing radiation. Aim 1 will address how HSF1 is regulated in mammary tumorigenesis. We will elucidate whether Hsf1 is constitutively activated in tumors because of aneuploidy-associated proteotoxicity by co-opting the signal transduction pathways observed in the heat shock response, or as a part of conventional HER2- mediated cancer signaling. In Aim 2, we will clarify how Hsf1 enters functional complexes in response to Her2, and affects global transcription. We will then elucidate the role of transcription mediated by HSF1 in the cancer cells, establishing HSF1 as a cancer stem cell factor, a player in epithelial/mesenchymal transition and a determinant of tumor metastasis (Aim 3). Finally, we will establish how Hsf1 determines cancer responses to ionizing radiation by testing a hypothesis that radiation resistance is linked to Hsf1 mediated control of cancer stem cells.