1 Cancer Science Institute of Singapore, National University of Singapore , Singapore, Singapore .
Antioxid Redox Signal. 2014 May 20;20(15):2326-46. doi: 10.1089/ars.2013.5295. Epub 2013 Nov 14.
Although earlier reports highlighted a tumor suppressor role for manganese superoxide dismutase (MnSOD), recent evidence indicates increased expression in a variety of human cancers including aggressive breast carcinoma. In the present article, we hypothesized that MnSOD expression is significantly amplified in the aggressive breast carcinoma basal subtype, and targeting MnSOD could be an attractive strategy for enhancing chemosensitivity of this highly aggressive breast cancer subtype.
Using MDA-MB-231 and BT549 as a model of basal breast cancer cell lines, we show that knockdown of MnSOD decreased the colony-forming ability and sensitized the cells to drug-induced cell death, while drug resistance was associated with increased MnSOD expression. In an attempt to develop a clinically relevant approach to down-regulate MnSOD expression in patients with basal breast carcinoma, we employed activation of the peroxisome proliferator-activated receptor gamma (PPARγ) to repress MnSOD expression; PPARγ activation significantly reduced MnSOD expression, increased chemosensitivity, and inhibited tumor growth. Moreover, as a proof of concept for the clinical use of PPARγ agonists to decrease MnSOD expression, biopsies derived from breast cancer patients who had received synthetic PPARγ ligands as anti-diabetic therapy had significantly reduced MnSOD expression. Finally, we provide evidence to implicate peroxynitrite as the mechanism involved in the increased sensitivity to chemotherapy induced by MnSOD repression.
These data provide evidence to link increased MnSOD expression with the aggressive basal breast cancer, and underscore the judicious use of PPARγ ligands for specifically down-regulating MnSOD to increase the chemosensitivity of this subtype of breast carcinoma.
尽管早期的报告强调了锰超氧化物歧化酶（MnSOD）的肿瘤抑制作用，但最近的证据表明，其在多种人类癌症中表达增加，包括侵袭性乳腺癌。在本文中，我们假设 MnSOD 在侵袭性乳腺癌基底亚型中表达显著扩增，并且靶向 MnSOD 可能是增强这种高度侵袭性乳腺癌亚型化疗敏感性的有吸引力的策略。
我们使用 MDA-MB-231 和 BT549 作为基底乳腺癌细胞系的模型，表明 MnSOD 的敲低降低了集落形成能力，并使细胞对药物诱导的细胞死亡敏感，而耐药性与 MnSOD 表达增加有关。为了尝试开发一种临床相关的方法来下调基底乳腺癌患者的 MnSOD 表达，我们利用过氧化物酶体增殖物激活受体γ（PPARγ）的激活来抑制 MnSOD 表达；PPARγ 激活显著降低了 MnSOD 的表达，增加了化疗敏感性并抑制了肿瘤生长。此外，作为 PPARγ 激动剂用于降低 MnSOD 表达的临床应用的概念验证，从接受合成 PPARγ 配体作为抗糖尿病治疗的乳腺癌患者获得的活检显示 MnSOD 表达显著降低。最后，我们提供了证据表明过氧亚硝酸盐是 MnSOD 抑制诱导的对化疗敏感性增加的相关机制。
这些数据提供了证据表明，MnSOD 表达增加与侵袭性基底乳腺癌有关，并强调了明智地使用 PPARγ 配体来特异性下调 MnSOD 以增加这种乳腺癌亚型的化疗敏感性。
