The overexpression and amplification of the protooncogene neu (ERBB2) play an important role in the development of aggressive breast cancer (BC) in humans. Ral‐interacting protein (RLIP), a modular stress‐response protein with pleiotropic functions, is overexpressed in several types of cancer, including BC. Here, we show that blocking RLIP attenuates the deleterious effects caused by the loss of the tumor suppressor p53 and inhibits the growth of human BC both in vitro and in vivo in MMTV‐neu mice. In addition, we show that treatment with the diet‐derived, RLIP‐targeting chemotherapeutic 2′‐hydroxyflavanone (2HF), alone or in combination with RLIP‐specific antisense RNA or antibodies, significantly reduced the cumulative incidence and/or burden of mammary hyperplasia and carcinoma in MMTV‐neu mice. 2HF treatment correlated with reduced tumor cell proliferation and increased apoptosis, and the average number of Ki67‐positive (proliferating) cells was significantly lower in the tumors of 2HF‐treated mice than in the tumors of control mice. Furthermore, targeting RLIP also resulted in the overexpression of E‐cadherin and the infiltration of CD3⁺ T cells into mammary tumors. Taken together, these results underscore the translational potential of RLIP‐targeting agents and provide a strong rationale to validate them in the clinic.

中文翻译：

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通过靶向 RLIP 预防 MMTV-neu 小鼠乳腺癌发生


原癌基因neu (ERBB2) 的过度表达和扩增在人类侵袭性乳腺癌 (BC) 的发展中发挥着重要作用。 Ral 相互作用蛋白 (RLIP) 是一种具有多效性功能的模块化应激反应蛋白，在包括 BC 在内的多种癌症中过度表达。在这里，我们表明，阻断 RLIP 可以减轻因肿瘤抑制因子 p53 缺失而引起的有害影响，并在 MMTV -neu小鼠体内和体外抑制人类 BC 的生长。此外，我们还发现，单独使用源自饮食的 RLIP 靶向化疗药物 2′-羟基黄烷酮 (2HF) 或与 RLIP 特异性反义 RNA 或抗体联合治疗，可显着降低乳腺增生的累积发生率和/或负担和 MMTV- neu小鼠的癌症。 2HF 治疗与肿瘤细胞增殖减少和细胞凋亡增加相关，2HF 治疗小鼠肿瘤中 Ki67 阳性（增殖）细胞的平均数量显着低于对照小鼠肿瘤。此外，靶向 RLIP 还导致 E-钙粘蛋白过度表达和 CD3 ⁺ T 细胞浸润到乳腺肿瘤中。总而言之，这些结果强调了 RLIP 靶向药物的转化潜力，并为在临床上验证它们提供了强有力的理由。