上海生化所最新Nature综述文章

　　

生物通报道：来自中科院上海生化与细胞所的研究人员回顾总结了几十年来人类对乳腺癌这个妇女中高发病率癌症的斗争中创造的分子疗法，并将这一文章发表在《Nature Reviews Endocrinology》杂志上。

文章的通讯作者是中科院上海生物化学研究所林胜祥客座研究员，其早年在中科院上海生物化学研究所酶学实验室从事博士后研究工作，现任加拿大拉瓦尔大学医学院终身教授，主要研究方向是结构生物学，研究工作包括十七羟类固醇脱氢酶家族的结构功能等。

选择性雌激素受体(ER)调制剂及芳香酶抑制剂已成为雌激素依赖型乳腺癌的两代标准分子疗法，取得了重要结果。多年来酶学与结构生物学对雌激素活化途径的系统研究提示，在雌激素生物合成中类固醇硫酸酯酶与17-羟类固醇脱氢酶的重要作用。硫酸酯酶抑制剂的I期乳腺癌临床试验结果令人鼓舞，支持了它们作为新靶点的意义。

在这篇文章中，研究人员回顾总结了几十年来人类对乳腺癌这个妇女中高发病率癌症的斗争中创造的分子疗法。它与早期诊断一起，将此病死亡率减低了40%（1990-1996与1975-1990相比较）。文章作者还提出了乳腺癌分子疗法的进一步方向。

选择性雌激素受体(ER)调制剂及芳香酶抑制剂已成为雌激素依赖型乳腺癌的两代标准分子疗法，取得了重要结果。多年来酶学与结构生物学对雌激素活化途径的系统研究提示，在雌激素生物合成中类固醇硫酸酯酶与17-羟类固醇脱氢酶的重要作用。硫酸酯酶抑制剂的I期乳腺癌临床试验结果令人鼓舞，支持了它们作为新靶点的意义。此文还讨论了雌激素受体信号传递系统及人表皮生长因子受体（HER）信号传递系统的“对话”，雌激素非依赖型癌的治疗，功能基因组学与RNA干扰对此癌治疗的研究和贡献。相关研究得到中加合作研究经费的支持。

除此之外，近期研究人员发现由于西兰花含有的一种化合物可以锁定肿瘤干细胞，这种蔬菜或掌握着预防甚至治疗乳腺癌的“钥匙”。

科学家首先给患有乳腺癌的小老鼠注射了从西蓝花中提取的不同浓度的萝卜硫素，然后通过几种方法评估其对肿瘤干细胞的作用，结果显示，注射萝卜硫素后，这些小老鼠体内的肿瘤干细胞的数量明显下降，而正常细胞则没有受到任何的干扰。

西蓝花的抗癌作用是近些年来西方国家及日本科学家研究的重要内容。日本国家癌症研究中心公布的抗癌蔬菜排行榜上，西蓝花名列前茅。美国《营养学》杂志上，也刊登了西蓝花能够有效预防前列腺癌的研究成果。

西蓝花的抗癌作用，主要归功于其中含有的硫葡萄糖甙，据说长期食用可以减少乳腺癌、直肠癌及胃癌等癌症的发病几率。

（生物通：万纹）

原文摘要：

Molecular therapy of breast cancer: progress and future directions
Sheng-Xiang Lin, Jiong Chen, Mausumi Mazumdar, Donald Poirier, Cheng Wang, Arezki Azzi & Ming Zhou

Top of pageAbstractBreast cancer is a major cause of death in Western women, with a 10% lifetime risk of the disease. Most breast cancers are estrogen-dependent. Molecular therapies for breast cancer have developed rapidly in the past few decades and future treatment strategies are being investigated. The selective estrogen receptor (ER) modulator tamoxifen, which until now has served as a standard therapy, functions not only as an estrogen antagonist but also as an estrogen agonist in terms of bone maintenance. Aromatase inhibitors have performed well in international trials and have become a new standard therapy for estrogen-dependent breast cancer. The systematic study of estrogen activation pathways suggests that the enzymes steroid sulfatase and 17β-hydroxysteroid dehydrogenase type 1, which both have pivotal roles in estrogen biosynthesis, are promising targets; the results of a phase I trial of steroid sulfatase inhibitors are encouraging. The activity of the human epidermal growth factor receptor (HER) pathway correlates negatively with that of the ER. HER2 is overexpressed in 22% of all breast cancers. In the decade since HER2 began being targeted, the monoclonal antibody trastuzumab has been used as well as pertuzumab and HER2 vaccines. Among the estrogen-independent breast cancers, the basal-like subtype has low survival, and therapeutic improvement is a priority. Crosstalk between ER and HER2 signaling pathways means that combinatory therapies may hold the key to enhancement of treatment responses. Other molecular therapies involving functional genomics and RNA interference studies also hold promise.

作者简介：

林胜祥

客座研究员

个人简介：
1982年-1984年中科院上海生物化学研究所酶学实验室博士后研究工作；1985年-1987年中科院上海生命科学院副研究员；1987年-1988年美国俄亥俄洲Case Western Reserve University生物化学系访问教授；1988年-1989年加拿大拉瓦尔大学科学工程学院生物化学系特聘教授；1989年-至今加拿大拉瓦尔大学科学工程学院分子内分泌实验室高级研究员；1990年-1993年加拿大拉瓦尔大学医学院基金制教授；1993年-1995年加拿大拉瓦尔大学医学院助理教授(待转终身)；1995年-1999年加拿大拉瓦尔大学医学院付教授(终身)；1999年-至今加拿大拉瓦尔大学医学院正教授(终身)。

研究方向：结构生物学

研究工作：
(1)十七羟类固醇脱氢酶家族的结构功能
首先报导了该家族一型酶的同等二聚体结构(Lin et al., 1992, J Bio Chem. 267:16182)，首次获得了此酶的晶体，及其第一个立体结构(Zhu et al. & Lin, 1993, J Mol Biol. 234:242; Ghosh et al. & Lin, 1995, Structure. 3:503)，这也是第一个报导的人胆固醇酶的结构。与三维结构紧密结合，深入研究了此酶的功能(Azzi et al, & Lin, 1996, Nature Struct Biol. 234:242; Han et al. & Lin, 2000, J Biol Chem. 275:1105; Gangloff et al. & Lin, 2003, FASEB J. 17:274)，设计并合成了迄今为止该酶的最高亲和力的杂交抑制剂( Ki 3M, Qiu et al. & Lin, 2002, FASEB J. 16:1829)。也解析了该家族五型酶的第一个晶体结构(Qiu et. Al. & Lin, 2004, Mol Endocrinol. 7:1998)。
(2)其他胆固醇酶的晶体学
首个人3α胆固醇脱氢酶三型(Nahoum et al., & Lin, 2001, J Biol Chem. 276:42091)，DHEA转硫酶与DHEA的复合物(Rehse et al. & Lin, 2002, Biochem J. 364:165)。
(3)其他与糖异生作用有关的酶，如肌肉果糖1-6二磷酸酶，氯酶素乙酰转移酶等的结构测定。
(4)对旦白质晶体生长普遍规律的贡献(Zhu et. Al., 2006, J Struct Biol. 154:297)。

代表性论文：

Blanchet, J., Lin, S.-X., & Zhorov, B.S. (2005) Mapping of steroid binding to 17b‑hydroxysteroid dehydrogenase type 1 using Monte Carlo energy minimization reveals alternative binding modes. Biochemistry, 44: 7218-7227.
Poirier, D., Boivin, R.P., Tremblay, M.R., Berube, M., Qiu, W., & Lin, S.-X. (2005) Estradiol hybrid compounds designed to inhibit type 1 17b‑hydroxysteroid dehydrogenase. J. Med. Chem., 48: 8134-8147.
Labrie, F., Luu-The, V., Belanger, A., Lin, S.-X., Simard, J., Pelletier, G., Labrie, C. (2005) Is Dehydroepiandrosterone a hormone? J. Endocrinol., 200: 169-196.
Poirier, D., Chang, H. J., Azzi, A., Boivin, R.P., & Lin, S.-X. (2006) Estrone and estradiol C-16 derivatives as inhibitors of type 1 17b‑hydroxysteroid dehydrogenase. Mol. Cell. Endocrin., 248: 236-238.
Lin, S.-X., Shi, R., Qiu, W., Azzi, A., Zhu, D.-W., Al Dabbagh, H. and Zhou, M. (2006) Structural Basis of the Multispecificity Demonstrated by 17β-HSD Types 1 and 5. Mol. Cell. Endocrin., 248: 38-46.
Zhu, D.-W., Garneau, A., Mazumdar, M., Zhou, M. Xu, G.-J. & Lin, S.-X. (2006) Attempts to rationalize protein crystallization using relative crystallizability. J. Struct. Biol., 154: 297-302.
Shi, R., Azzi, A., Gilbert, C., Boivin, G., Lin, S.-X. (2006) Three-dimensional modeling of cytomegalovirus DNA polymerase and preliminary analysis of drug resistance. Proteins., 64: 301-307.
Qiu, W., Zhou, M, Mazumdar, M., Azzi, A., Ghanmi,D., Luu-The, V., Labrie, F. and Lin, S-X. (2007) Structure-based inhibitor design for an enzyme which binds different steroids: a potent inhibitor for human type 5 17b-hydroxysteroid dehydrogenase. J. Biol. Chem., 282: 8368-79.
Zhou, M., Azzi, A., Xia, X., Wang, E.D., and Lin, S.-X. (2007) Crystallization and preliminary X-ray diffraction analysis of E. coli arginyl-tRNA synthetase in complex with a tRNAArg. Amino Acids., 32: 479-82.
Azzi, A. & Lin, S.-X. (2007) Structure function analysis of West Nile Virus RNA dependent RNA polymerase: Molecular model and implications for drug design. Medicinal Chemistry, 3: 455-59.
Mausumi, M., Zhou, M., Zhu, D-W, Azzi, A. and Lin, S.-X. (2007) Crystallogenesis of steroid-converting enzymes and their complexes: enzyme-ligand interaction studies and inhibitor design facilitated by complex structures. Crystal Growth and design, 7: 2206-2212.
Lin, S.-X., McPherson, A. & Giegé, R. (2007) Good crystals, still a challenge for structural biology. Crystal Growth and design, 7: 2124-2125.
Wang, T. et al., and Lin, S.-X. (2007) Purification, refolding crystallization and diffraction analysis of the native and seleno-methionine-substituted rat epidymal-specific lipocalin. Crystal Growth and design, 7: 2167-2170.
Lin, S.-X., Giege, R., and Bergfors, T. (2007) Progress in Macromolecular Crystallogenesis. Crystal Growth and design, 7: 2123.
Lin, S.-X., Giege, R., and Bergfors, T. (2007) Special Section: Macromolecular Crystallogenesis at ICCBM11. Crystal Growth and design, 7: 2123-2253.
Wang, T., Zou, Y.-S., Zhu, D.-W., Azzi, A., Liu, W.-Y. and Lin, S-X. (2008) Cinnamomin separation, crystallization and preliminary X-ray diffraction results. Amino Acids, 34:239-43.
Fournier, D., Poirier, D., Mazumdar, M., Lin, S.-X. (2008) Design and synthesis of bisubstrate
inhibitors of type 1 17β-hydroxysteroid dehydrogenase: Overview and perspectives. Eur. J. Med.Chem. 2298-2306.
Lin, Y.-B., Zhu, D.-W., Wang, T., Song, J., Zou, Y.-S., Zhang, Y.-L., and Lin, S.-X. (2008) An extensive study of protein phase diagram modification: increasing macromolecular crystallizability by temperature screening, Cryst. Growth & Design, 8:4277-4283.
Azzi, Arezki, Wang, Tao, Zhu, Dao-Wei, Zou,Yong-Shui, Liu, Wang-Yi and Lin, Sheng-Xiang. (2009) Crystal Structure of Native Cinnamomin Isoform III and its comparison with other Ribosome Inhibiting Proteins. Proteins: Structure, function and bio-information, 74: 250-255.
Aka, Juliette, Mazumdar, Mausumi. & Lin, Sheng-Xiang (2009) Reductive 17beta-hydroxysteroid dehydrogenases in the sulfatase pathway: critical in the cell proliferation of breast cancer. Mol. Cell. Endocrinol. 301: 183-190.
Rui Bao, Cong-Zhao Zhou, Chunhui Jiang, Sheng-Xiang Lin, Cheng-Wu Chi, and Yuxing Chen (2009). The ternary structure of the double-headed arrowhead protease inhibitor API-A complexed with two trypsins reveals a novel reactive site conformation. J. Biol. Chem. 284: 26676-26684.
Mazumdar, Diane Fournier, Dao-Wei Zhu, Christine Cadot, Donald Porier, Sheng-Xiang Lin. (2009) Binary and ternary crystal structure analyses of a novel inhibitor of 17β-HSD type1: a lead compound for breast cancer therapy. Biochem. J. 424: 357-366.
Aka, Juliette, Mazumdar, Mausumi, Chen, Chang-Qing, Poirier, Donald and Lin, Sheng-Xiang (2010)17β-hydroxysteroid dehydrogenase Type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production. Mol. Endocrinol. 24:832-45.
Ding, Fei-Xiang; Xu, Ye-Fen; Azzi, Arezki; Zhu, Dao-Wei; Rehse, Peter; Chen, Chang-Qin; Sun, ShuHan; Lin, Sheng-Xiang (2010) Crystallization of the membrane-associated Annexin B1: roles of additive screen, dynamic light scattering and bioactivity assay. Cryst. Growth & Design. DOI: 10.1021/cg901046f.
Martin, Mélanie, Azzi, Arezki, Lin, Sheng-Xiang, and Boivin, G. (2010) Opposite impact of two DNA polymerase mutations found in a clinical cytomegalovirus isolate resistant to Ganciclovir and Foscarnet on replicative capacity and polymerase activity. Antiviral Therapy, in press.