HMGA1 in Tumor Progression in Breast Cancer

描述（由申请人提供）：尽管在转移性乳腺癌的检测和治疗方面取得了进展，但这种疾病的死亡率仍然很高，因为目前的治疗方法受到对治疗具有耐药性和能够转移进展的癌细胞的出现的限制。越来越多的证据表明，这些细胞的发展，部分是因为它们的行为像干细胞，从而逃避了针对快速分裂的肿瘤细胞的治疗引起的细胞死亡。该建议旨在阐明乳腺癌转移进展和“干性”的重要分子途径，以确定新的治疗靶点和生物标志物。我们的重点是HMGA1癌基因，因为最近的研究结果表明它在这两个过程中都起着关键作用。该基因编码HMGA1a和HMGA1b染色质结合蛋白，其功能是调节基因表达。HMGA1在胚胎发生期间高表达，但在成人组织中不表达。引人注目的是，HMGA1在迄今研究的几乎所有高级别（低分化）人类癌症中也过表达。我们首先确定HMGA1在正常乳腺细胞的培养细胞中诱导致癌转化。HMGA1也会在转基因小鼠中引起侵袭性癌症，并促进MCF-7乳腺细胞的上皮到间充质转化（EMT）。相反，抑制其表达可阻断高级别人乳腺癌细胞系的转化表型，并在某些肿瘤模型中阻止转移进展。最近的一项研究还发现HMGA1是在高级别/低分化乳腺癌和正常胚胎干细胞中富集的9个核心转录因子之一，进一步表明HMGA1是乳腺癌进展和干细胞的关键调节因子。综上所述，这些发现表明HMGA1调控的转录网络在乳腺癌和干细胞中都维持着原始的低分化状态。基于这些发现，我们假设HMGA1通过诱导维持未分化的“茎样”表型的转录网络来驱动肿瘤进展。在这里，我们提出研究以确定HMGA1是否是转移性乳腺癌的生物标志物和潜在的治疗靶点。我们还将开始研究HMGA1如何驱动乳腺癌的肿瘤进展。利用我们独特的资源，我们提出以下具体目标：1)利用组织微阵列与原发性乳腺肿瘤和bbb500例患者的详细临床数据，确定HMGA1是否可以作为晚期、低分化乳腺癌的生物标志物(2)。利用功能获得/功能丧失的方法阐明HMGA1在肿瘤进展和干细胞表型中的作用；确定HMGA1在转移性乳腺癌中的分子特征，开始明确下游转录靶点的功能意义。我们的研究结果将阐明在肿瘤进展中重要的新分子通路，并将导致发现可能靶向治疗转移性乳腺癌的细胞通路。

DESCRIPTION (provided by applicant): Despite progress in the detection and treatment of metastatic breast cancer, mortality from this disease remains high because current therapies are limited by the emergence of cancer cells that are resistant to treatment and capable of metastatic progression. Increasing evidence suggests that these cells develop, in part, because they behave like stem cells and thereby evade cell death induced by therapies which target rapidly dividing tumor cells. This proposal is directed at elucidating molecular pathways important in metastatic progression and "stemness" in breast cancer with the goal of identifying novel therapeutic targets and biomarkers. Our focus is the HMGA1 oncogene because recent findings suggest that it plays a critical role in both of these processes. This gene encodes the HMGA1a and HMGA1b chromatin binding proteins, which function in modulating gene expression. HMGA1 is highly expressed during embryogenesis, but not in adult tissues. Strikingly, HMGA1 is also overexpressed in virtually all high-grade (poorly differentiated) human cancers studied to date. We first established that HMGA1 induces oncogenic transformation in cultured cells derived from normal breast cells. HMGA1 also causes aggressive cancers in transgenic mice and promotes an epithelial-to-mesenchymal transition (EMT) in MCF-7 breast cells. Conversely, inhibiting its expression blocks transformation phenotypes in high-grade, human breast cancer cell lines and prevents metastatic progression in some tumor models. A recent study also found that HMGA1 is among a list of 9 core transcription factors enriched in high-grade/poorly differentiated breast cancers and normal embryonic stem cells, further implicating HMGA1 as a key regulator in breast cancer progression and stem cells. Taken together, these findings suggest that HMGA1 orchestrates transcriptional networks that maintain a primitive, poorly differentiated state, both in breast cancer and stem cells. Based on these findings, we hypothesize that HMGA1 drives tumor progression by inducing transcriptional networks that maintain an undifferentiated, "stem-like" phenotype. Here, we propose studies to determine if HMGA1 is a biomarker and potential therapeutic target in metastatic breast cancer. We will also begin studies to determine how HMGA1 drives tumor progression in breast cancer. Using our unique resources, we propose the following Specific Aims: 1.) Determine if HMGA1 can serve as a biomarker for more advanced, less differentiated breast cancer using a tissue microarray with primary breast tumors and detailed clinical data from >500 patients, 2.) Elucidate the role of HMGA1 in tumor progression and the stem-cell phenotype using gain-of- function/loss-of-function approaches, and, 3.) Identify the molecular signature of HMGA1 in metastatic breast cancer and begin to define the functional significance of downstream transcriptional targets. Results from our studies will elucidate novel molecular circuitry important in tumor progression and should lead to the discovery of cellular pathways that could be targeted in therapy for metastatic breast cancer. PUBLIC HEALTH RELEVANCE: Although metastatic breast cancer is a common and highly lethal cancer that affects women worldwide, the cellular pathways that mediate tumor progression and resistance to therapy are poorly understood. To address this knowledge gap, we propose to study the HMGA1 oncogene, which is highly expressed in advanced breast cancer and embryonic stem cells. Results from our studies should enhance our understanding of how breast cancer progresses and provide the basis to design better therapies directed at these resistant cells.