HMGA2：一个潜在预测乳腺癌患者阿霉素治疗疗效的标记物及其分子机理的研究

Breast cancer is one of the most common cancer diagnosed in women in China. Once diagnosed, it is treated by a combination of modalities including surgery, chemotherapy, radiation and hormonal therapy. Treatment is influenced by age, menopausal status, pathology (eg. nuclear and histological grades), estrogen and progesterone receptor status and Her2/neu gene amplification. For over 30 years, doxorubicin (Dox) has been the mainstay in the treatment of breast cancer. Its clinical benefits are often plagued by severe side effects including myelosuppression, hepatic toxicity and congestive heart failure, which may require dose reduction or even discontinuation of the drug. Hence, there is a need to identify patient populations or other synergistic factors to improve treatment outcome and to minimize undesired side effects. In order to improve clinical outcomes with Dox-treatment, we have identified the high-mobility group A2 (HMGA2) expression as a therapeutic marker. HMGA2 has been known to be an indicator for poor prognosis and has also been associated with tumor metastasis in breast cancer. We have found that HMGA2 expression sensitizes breast cancer cells to Dox-treatment and may provide a novel role as a therapeutic marker for rendering Dox chemosensitivity in breast cancer treatment. The underlying mechanism of HMGA2 in mammary epithelial tumorigenesis is largely unknown. Our preliminary findings suggest that high levels of endogenous HMGA2 expression sensitizes breast cancer HS578T cells to Dox by modulating cellular response to DNA damages, such as DNA double-strand breaks. Our central hypothesis is that Dox utilizes this HMGA2-dependent pathway to enhance its cytotoxicity and that breast cancer cells constitutively expressing HMGA2 leads to the accumulation of DNA damages and cancer tumorigenesis. We will retrospectively and prospectively correlate HMGA2 expression in samples from patients with their response to Dox regimen. Molecular analyses on cellular responses to Dox-elicited genotoxic stress will add useful information to the mechanism underlying HMGA2-mediated Dox chemosensitivity. Conceivably, HMGA2 could potentially be used as a molecular marker for identifying Dox-responsive breast cancer patients thus achieving better pharmacotherapeutic outcomes and allowing patients and physicians to make more informative treatment decisions on selecting optimal therapeutic strategies.

30年以来，以阿霉素为基础的化疗方案一直是乳癌化疗的基石。但阿霉素有很多的副作用：骨髓抑制、肝损及心衰等。因此有必要寻找特异的标记物来鉴定适合化疗的人群以提高疗效降低副反应。HMGA2高表达与乳癌不良预后密切相关。我们发现HMGA2高表达可提高乳癌细胞对阿霉素的敏感性，提示HMGA2有可能作为一个判断阿霉素疗效的指标。HMGA2在乳腺肿瘤发展过程中的作用机制目前尚不清楚。我们发现高表达的HMGA2通过调节细胞对DNA损伤的反应，来提高乳癌细胞HS578T对阿霉素的敏感性。本研究中心假设：阿霉素通过依赖HMGA2的途径来提高细胞毒性；HMGA2促进DNA损伤积聚和肿瘤发展。我们将分析乳癌患者对阿霉素的敏感性和HMGA2表达之间的关系。随后在分子水平上的分析将有助于理解HMGA2介导阿霉素增敏的机制。可预见的是：HMGA2能用于判断阿霉素治疗的敏感性，有助于制定优化的化疗策略，寻找新的靶分

HMGA2作为一个非组蛋白染色体蛋白，参与了体内各种生物过程，并在多种肿瘤中表达上调。然而，HMGA2蛋白水平与乳腺癌预后的关系还没有被系统的报道过。我们从浙江大学医学院附属第二医院收集了273例乳腺癌标本作为试验组，来自上海生物芯片国家工程中心的310例乳腺癌标本作为验证组作进一步研究。我们发现HMGA2蛋白的表达与乳腺癌的病理分化程度及预后显著相关。通过亚组分析表明高表达HMGA2与预后差的关系在II/III期乳腺癌，病理分级为I级的乳腺癌以及非三阴性乳腺癌病例中显著相关。在体外实验研究表明，HMGA2蛋白表达促进乳腺癌细胞的侵袭和迁移，HMGA2的表达还可以通过刺激P53 (Ser15)的表达来减少阿霉素对癌细胞的伤害。总的来说，我们的研究提示HMGA2可以作为治疗乳腺癌前的预后不良的标志物和为研究治疗乳腺癌靶点药物提供新的思路。