Determinants for genome-wide epigenomics in metastatic breast cancer

乳腺癌是美国女性最常见的癌症，每年导致约4万人死亡。在拟议的研究中，我们将重点关注乳腺癌，并确定哪些表观基因组变化导致乳腺癌获得转移活性以及这些变化是如何建立的。染色质的表观遗传修饰与个体基因的表达状态有关。在这里，我们提出了一个范式转换的想法，即参与全局基因调控的单个分子是大规模表观遗传变化的基础，这些变化通过结合作为染色体标记的特殊DNA序列子集，驱动肿瘤细胞向侵袭性转移性肿瘤细胞的转化。我们发现胸腺细胞中的基因组组织者SATB1是通过改变乳腺癌转移的关键决定因素

Breast cancer is the most common cancer in women in the United States, causing ~40,000 deaths each year. In the proposed study, we will focus on breast cancer and determine what epigenomic changes cause breast cancer to acquire metastatic activity and how the changes are established. Epigenetic modifications of chromatin are associated with the expression status of individual genes. Here we propose a paradigm-shifting idea that a single molecule involved in global gene regulation underlies the massive epigenetic changes that drive the transformation of a tumor cell to aggressive metastastic tumor cells through binding to a subset of specialized DNA sequence that functions as chromosomal marks. We identified SATB1, a genome organizer in thymocytes, to be a key determinant in breast cancer metastasis by altering expression of ~1000 genes, including many associated with poor prognosis. We will test a hypothesis that SATB1 causes progression of non-aggressive breast cancer to metastatic cancer by establishing genome-wide changes in epigenetic marks through global re-organization of higher-order chromatin structure. We further hypothesize that such re-organization involves SATB1 interaction with highly conserved, specialized DNA sequences called base unpairing regions (BURs), distributed throughout the human genome. These BURs may function as chromosome "marks" to which chromatin modifiers are recruited, thus resulting in specific epigenetic modifications throughout the genome characteristic of aggressive breast cancer. We will adopt a global mapping approach by high-throughput sequencing to map all putative BURs across the human genome and identify those that are bound by SATB1in aggressive breast cancer cells versus those in activated human T helper cells, a non cancerous cell-type where SATB1 is normally expressed. We will subsequently determine genome-wide histone modifications in SATB1-expressing metastatic cancer and SATB1-deficient, non- aggressive breast cancer cells to determine whether aggressive cancer-associated changes in epigenetic marks are centered at SATB1-bound BURs. From the proposed research, we will define the role of BURs in establishing metastatic breast cancer-specific epigenetic marks through interaction with SATB1. These experiments will provide fundamental insight into disease progression that should be useful for developing future therapies.