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化生型乳腺癌属于恶性程度极高的三阴性乳腺癌亚型之一，其中部分或全部腺癌转变为非腺癌（例如梭状细胞癌、鳞状细胞癌、异源细胞癌）。既往研究已经发现，乳腺细胞外基质相关蛋白6（CCN6）或WNT1诱导信号通路蛋白3（WISP3）基因敲除小鼠可以发生梭形细胞和鳞状细胞分化的乳腺癌，与人类化生型乳腺癌共同受到癌胚蛋白（肿瘤胚胎抗原蛋白）胰岛素样生长因子2（IGF2）信使核糖核酸（mRNA）结合蛋白（IGF2BP2或IMP2）和高迁移率蛋白2（HMGA2）的调节。 2018年9月15日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表美国密歇根大学医学院罗格癌症中心的研究报告，分析了体外和体内CCN6、IMP2、HMGA2蛋白之间的功能关系，及其表达于人类化生型乳腺癌组织标本的水平。 该研究利用重组CCN6蛋白或载体，对小鼠乳腺肿瘤病毒（MMTV）cre携带CCN6纯合fl/fl肿瘤和梭状三阴性乳腺癌细胞株进行处理。通过稳定CCN6小发夹核糖核酸（shRNA）敲低，利用人类乳腺上皮细胞shRNA下调IMP2，并且测定侵袭能力和黏附能力。将31例人类化生型乳腺癌组成组织微阵列（芯片）对CCN6、IMP2、HMGA2进行免疫染色。 结果发现，CCN6可以控制MMTV肿瘤、MDA-MB-231和468、人类乳腺上皮细胞的IMP2和HMGA2蛋白表达。CCN6重组蛋白可以抑制IMP2和HMGA2蛋白表达，并且抑制体内MMTV肿瘤生长。利用shRNA敲低IMP2足以逆转人类乳腺上皮细胞CCN6敲低产生的侵袭能力。对美国癌症基因组图谱（TCGA）乳腺癌队列1238例患者分析表明，化生型乳腺癌与其他亚型乳腺癌相比，IMP2和HMGA2的表达水平被显著提高。对于临床标本，低CCN6常见于IMP2和HMGA2表达水平高的梭状和鳞状分化肿瘤。 因此，这些数据揭示了化生型乳腺癌的发病机制，并且证明了具有生物标志和治疗意义的致癌新通路及其靶点：CCN6→IMP2/→HMGA2。 最后，还是需要强调，三阴性乳腺癌并非一种疾病，而是由一大类不同疾病组成。不同的三阴性乳腺癌，有不同的通路和靶标，需要不同的治疗方法。有人抱怨，每天都有新的通路和靶标被发现，究竟哪个有用？只能告诉你：有人住高楼，有人在深沟，有人光万丈，有人一身锈。靶点万千种，浮云莫去求，通路若彩虹，遇上方知有。当癌症来找上门的时候，我们要做的事情是选择相信，相信科学、相信医生、相信自己、也要相信因果。 Breast Cancer Res Treat. 2018 Sep 15. CCN6 regulates IGF2BP2 and HMGA2 signaling in metaplastic carcinomas of the breast. Emily R. McMullen, Maria E. Gonzalez, Stephanie L. Skala, Mai Tran, Dafydd Thomas, Sabra I. Djomehri, Boris Burman, Kelley M. Kidwell, Celina G. Kleer. University of Michigan Medical School, Rogel Cancer Center, Ann Arbor, USA. PURPOSE: Metaplastic breast carcinomas are an aggressive subtype of triple-negative breast cancer (TNBC) in which part or all of the adenocarcinoma transforms into a non-glandular component (e.g., spindled, squamous, or heterologous). We discovered that mammary-specific Ccn6/Wisp3 knockout mice develop mammary carcinomas with spindle and squamous differentiation that share upregulation of the oncofetal proteins IGF2BP2 (IMP2) and HMGA2 with human metaplastic carcinomas. Here, we investigated the functional relationship between CCN6, IGF2BP2, and HMGA2 proteins in vitro and in vivo, and their expression in human tissue samples. METHODS: MMTV-cre;Ccn6fl/fl tumors and spindle TNBC cell lines were treated with recombinant CCN6 protein or vehicle. IGF2BP2 was downregulated using shRNAs in HME cells with stable CCN6 shRNA knockdown, and subjected to invasion and adhesion assays. Thirty-one human metaplastic carcinomas were arrayed in a tissue microarray (TMA) and immunostained for CCN6, IGF2BP2, and HMGA2. RESULTS: CCN6 regulates IGF2BP2 and HMGA2 protein expression in MMTV-cre;Ccn6fl/fl tumors, in MDA-MB-231 and -468, and in HME cells. CCN6 recombinant protein reduced IGF2BP2 and HMGA2 protein expression, and decreased growth of MMTV-cre;Ccn6fl/fl tumors in vivo. IGF2BP2 shRNA knockdown was sufficient to reverse the invasive abilities conferred by CCN6 knockdown in HME cells. Analyses of the TCGA Breast Cancer Cohort (n=1238) showed that IGF2BP2 and HMGA2 are significantly upregulated in metaplastic carcinoma compared to other breast cancer subtypes. In clinical samples, low CCN6 is frequent in tumors with high IGF2BP2/HMGA2 with spindle and squamous differentiation. CONCLUSIONS: These data shed light into the pathogenesis of metaplastic carcinoma and demonstrate a novel CCN6/IGF2BP2/HMGA2 oncogenic pathway with biomarker and therapeutic implications. KEYWORDS: Breast cancer CCN6 WISP3 IGF2BP2 HMGA2 Metaplastic DOI: 10.1007/s10549-018-4960-2
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