Madrid Félix Fernández, Grossman Lawrence I, Aras Siddhesh
Department of Medicine, Division of Rheumatology, Wayne State University School of Medicine, Detroit, MI 48201 USA.
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201 USA.
J Cancer Immunol (Wilmington). 2020 Dec;2(4):138-158. doi: 10.33696/cancerimmunol.2.027.
We review here the evidence for participation of mitochondrial autoimmunity in BC inception and progression and propose a new paradigm that may challenge the prevailing thinking in oncogenesis by suggesting that mitochondrial autoimmunity is a major contributor to breast carcinogenesis and probably to the inception and progression of other solid tumors. It has been shown that MNRR1 mediated mitochondrial-nuclear function promotes BC cell growth and migration and the development of metastasis and constitutes a proof of concept supporting the participation of mitochondrial autoimmunity in breast carcinogenesis. The resemblance of the autoantibody profile in BC detected by IFA with that in the rheumatic autoimmune diseases suggested that studies on the autoantibody response to tumor associated antigens and the characterization of the mtDNA- and nDNA-encoded antigens may provide functional data on breast carcinogenesis. We also review the studies supporting the view that a panel of autoreactive nDNA-encoded mitochondrial antigens in addition to MNRR1 may be involved in breast carcinogenesis. These include GAPDH, PKM2, GSTP1, SPATA5, MFF, ncRNA PINK1-AS/DDOST as probably contributing to BC progression and metastases and the evidence suggesting that DDX21 orchestrates a complex signaling network with participation of JUND and ATF3 driving chronic inflammation and breast tumorigenesis. We suggest that the widespread autoreactivity of mtDNA- and nDNA-encoded mitochondrial proteins found in BC sera may be the reflection of autoimmunity triggered by mitochondrial and non-mitochondrial tumor associated antigens involved in multiple tumorigenic pathways. Furthermore, we suggest that mitochondrial proteins may contribute to mitochondrial dysfunction in BC even if mitochondrial respiration is found to be within normal limits. However, although the studies show that mitochondrial autoimmunity is a major factor in breast cancer inception and progression, it is not the only factor since there is a multiplex autoantibody profile targeting centrosome and stem cell antigens as well as anti-idiotypic antibodies, revealing the complex signaling network involved in breast carcinogenesis. In summary, the studies reviewed here open new, unexpected therapeutic avenues for cancer prevention and treatment of patients with cancer derived from an entirely new perspective of breast carcinogenesis.
我们在此回顾线粒体自身免疫参与乳腺癌发生和发展的证据，并提出一种新的范式，该范式可能会挑战肿瘤发生的主流观点，即线粒体自身免疫是乳腺癌发生的主要因素，可能也是其他实体瘤发生和发展的主要因素。已有研究表明，MNRR1介导的线粒体-核功能促进乳腺癌细胞的生长、迁移以及转移的发展，这构成了支持线粒体自身免疫参与乳腺癌发生的概念验证。免疫荧光法检测到的乳腺癌自身抗体谱与风湿性自身免疫疾病中的自身抗体谱相似，这表明对肿瘤相关抗原的自身抗体反应以及线粒体DNA和核DNA编码抗原的特征研究可能为乳腺癌发生提供功能数据。我们还回顾了一些研究，这些研究支持这样一种观点，即除MNRR1外，一组自身反应性核DNA编码的线粒体抗原可能参与乳腺癌的发生。这些抗原包括甘油醛-3-磷酸脱氢酶（GAPDH）、丙酮酸激酶M2（PKM2）、谷胱甘肽S-转移酶P1（GSTP1）、精子发生相关蛋白5（SPATA5）、线粒体融合因子（MFF）、非编码RNA PINK1-AS/双功能天冬酰胺基tRNA合成酶（DDOST），它们可能促进乳腺癌的进展和转移，还有证据表明解旋酶21（DDX21）与JUND和ATF3共同参与一个复杂的信号网络，驱动慢性炎症和乳腺肿瘤发生。我们认为，在乳腺癌血清中发现的线粒体DNA和核DNA编码的线粒体蛋白广泛的自身反应性，可能是由参与多种致癌途径的线粒体和非线粒体肿瘤相关抗原引发的自身免疫的反映。此外，我们认为即使发现线粒体呼吸在正常范围内，线粒体蛋白也可能导致乳腺癌中的线粒体功能障碍。然而，尽管研究表明线粒体自身免疫是乳腺癌发生和发展的主要因素，但它不是唯一因素，因为存在针对中心体和干细胞抗原的多重自身抗体谱以及抗独特型抗体，揭示了参与乳腺癌发生的复杂信号网络。总之，这里回顾的研究从乳腺癌发生的全新视角为癌症预防和癌症患者的治疗开辟了新的、意想不到的治疗途径。
