Background ErbB2 breast cancer still remains an unmet need due to primary and/or acquired resistance to current treatment strategies. MEDICA compounds consist of synthetic long-chain α,ω-dicarboxylic acids previously reported to suppress breast cancer in PyMT transgenic mice. Methods MEDICA efficacy and mode of action in the ErbB2 context was studied in ErbB2 transgenic mice and human breast cancer cells. Results MEDICA treatment is shown here to suppress ErbB2 breast tumors and lung metastasis in ErbB2/neu MMTV transgenic mice, to suppress ErbB2/neu xenografts in nod/scid mice, and to suppress survival of AU565 and BT474 human ErbB2 breast cancer cells. Suppression of ErbB2 breast tumors by MEDICA is due to lipid raft disruption with loss of ErbB family members, including EGFR, ErbB2, and ErbB3. In addition, MEDICA inhibits mTORC1 activity, independently of abrogating the ErbB receptors and their signaling cascades. The double hit of MEDICA in abrogating ErbB and mTORC1 is partly accounted for by targeting mitochondria complex I. Conclusions Mitochondrial targeting by MEDICA suppresses ErbB2 breast tumors and metastasis due to lipid raft disruption and inhibition of mTORC1 activity. Inhibition of mTORC1 activity by MEDICA avoids the resistance acquired by canonical mTORC1 inhibitors like rapalogs or mTOR kinase inhibitors.

中文翻译：

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线粒体靶向治疗 ErbB2 乳腺癌

背景 由于对当前治疗策略的原发性和/或获得性耐药性，ErbB2 乳腺癌仍然没有得到满足。MEDICA 化合物由合成的长链 α,ω-二羧酸组成，以前曾报道过它可以抑制 PyMT 转基因小鼠的乳腺癌。方法 MEDICA 在 ErbB2 环境中的功效和作用方式在 ErbB2 转基因小鼠和人乳腺癌细胞中进行了研究。结果 这里显示 MEDICA 治疗可抑制 ErbB2/neu MMTV 转基因小鼠的 ErbB2 乳腺肿瘤和肺转移，抑制 nod/scid 小鼠的 ErbB2/neu 异种移植物，并抑制 AU565 和 BT474 人 ErbB2 乳腺癌细胞的存活。MEDICA 对 ErbB2 乳腺肿瘤的抑制是由于脂筏破坏导致 ErbB 家族成员（包括 EGFR、ErbB2 和 ErbB3）的丧失。此外，MEDICA 抑制 mTORC1 活性，与消除 ErbB 受体及其信号级联反应无关。MEDICA 在消除 ErbB 和 mTORC1 方面的双重打击部分归因于靶向线粒体复合物 I。结论 MEDICA 的线粒体靶向抑制了 ErbB2 乳腺肿瘤和转移，因为脂筏破坏和 mTORC1 活性的抑制。MEDICA 对 mTORC1 活性的抑制避免了经典 mTORC1 抑制剂（如 rapalogs 或 mTOR 激酶抑制剂）获得的耐药性。