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化学预防是指对无症状者使用药物、营养素（包括无机盐）、生物制剂或其他天然物质作为一级、二级预防为主的措施，例如：用阿司匹林预防心脏病、脑卒中以及可能的肿瘤，绝经后女性用雌激素预防骨质疏松和心脏病，他莫昔芬用于女性乳腺癌的化学预防，维生素用于肿瘤的预防。这方面最早的研究可以回溯到1929年发表的芥子气抑制焦油所致皮肤癌。 癌症的化学预防研究从1970年代兴起，直至美国食品药品管理局（FDA）批准第一个乳腺癌化学预防药物他莫昔芬、美国国家卫生研究院（NIH）正式设立化学/饮食预防（CDP）评审分部，标志着癌症化学预防成为癌症研究的重要领域。 虽然针对雌激素和雌激素受体通路的化学预防药物对雌激素受体阳性乳腺癌有效，但是激素受体阴性乳腺癌如HER2阳性乳腺癌的预防，仍然是重要问题。既往研究已经证实，小鼠乳腺肿瘤病毒（MMTV）-HER2转基因小鼠使用针对EGFR（erbB-1）和HER2（erbB-2）的拉帕替尼可抑制乳腺肿瘤生长。然而，该预防作用通过长时间大剂量用药实现。对大剂量长期用药的耐受性可能妨碍其临床潜力。 2017年1月6日，美国生物医学中心旗下《实验与临床癌症研究杂志》在线发表北卡罗来纳中央大学、河南科技大学第一附属医院、俄克拉荷马大学健康科学中心的研究报告，测试了一种新型短期化学预防策略，将拉帕替尼用于MMTV-HER2小鼠癌前危险窗口期。 该研究先用拉帕替尼处理经过培养的细胞，以尝试拉帕替尼在体外的抗增殖作用，再用同基因肿瘤移植模型开始探索拉帕替尼在MMTV-HER2小鼠体内的抗肿瘤发生作用。然后，测试了≥16周龄的MMTV-HER2小鼠短期使用拉帕替尼（100mg/kg/d，持续8周）预防乳腺肿瘤生长的效果。 结果发现，在同基因肿瘤移植模型中，拉帕替尼显著抑制肿瘤细胞增殖。此外，与对照小鼠相比，短期使用拉帕替尼对小鼠产生终身保护效应，可延长肿瘤潜伏期。 该研究进一步确定拉帕替尼通过减少溴脱氧尿嘧啶核苷（溴化去氧尿苷）进入细胞核并抑制乳腺形态发生变化，从而延缓小鼠肿瘤进展。 分子分析表明，拉帕替尼抑制了癌前乳腺组织中的EGFR、HER3/erbB-3、HER2、Akt1、Erk1/2磷酸化和表达。此外，拉帕替尼强有力抑制了癌前乳腺组织中的雌激素受体α磷酸化和表达、雌激素受体靶基因转录。拉帕替尼还抑制了乳腺癌干细胞，减少了肿瘤球形成和乙醛脱氢酶阳性细胞数量。乙醛脱氢酶的表达与乳腺癌的发生、发展、预后和转移密切相关，而且在乳腺癌干细胞表面高表达。 因此，该研究表明，在肿瘤进展之前，使用EGFR和HER2靶向药物短暂治疗，可以通过同时抑制HER2和雌激素受体信号通路以及后续重编程（已分化细胞的核基因组恢复其分化前的功能状态），从而产生对乳腺肿瘤的终身预防作用。该研究结果支持进一步临床测试，以探讨更短期使用拉帕替尼对预防HER2致癌作用的获益。 J Exp Clin Cancer Res. 2017 Jan 6;36(1):6. Short-term early exposure to lapatinib confers lifelong protection from mammary tumor development in MMTV-erbB-2 transgenic mice. Ma Z, Parris AB, Xiao Z, Howard EW, Kosanke SD, Feng X, Yang X. North Carolina Central University, Kannapolis, NC, USA; First Affiliated Hospital of Henan University of Sciences and Technology, Luoyang, China; University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. BACKGROUND: Although chemopreventative agents targeting the estrogen/estrogen receptor (ER) pathway have been effective for ER+ breast cancers, prevention of hormone receptor-negative breast cancers, such as Her2/erbB-2+ breast cancers, remains a significant issue. Previous studies have demonstrated that administration of EGFR/erbB-2-targeting lapatinib to MMTV-erbB-2 transgenic mice inhibited mammary tumor development. The prevention, however, was achieved by prolonged high dose exposure. The tolerance to high dose/long-term drug administration may hinder its potential in clinical settings. Therefore, we aimed to test a novel, short-term chemopreventative strategy using lapatinib during the premalignant risk window in MMTV-erbB-2 mice. METHODS: We initially treated cultured cells with lapatinib to explore the anti-proliferative effects of lapatinib in vitro. We used a syngeneic tumor graft model to begin exploring the in vivo anti-tumorigenic effects of lapatinib in MMTV-erbB-2 mice. Then, we tested the efficacy of brief exposure to lapatinib (100 mg/kg/day for 8 weeks), beginning at 16 weeks of age, in the prevention of mammary tumor development in MMTV-erbB-2 mice. RESULTS: In the syngeneic tumor transplant model, we determined that lapatinib significantly inhibited tumor cell proliferation. Furthermore, we demonstrated that short-term lapatinib exposure resulted in life-long protective effects, as supported by increased tumor latency in lapatinib-treated mice compared to the control mice. We further established that delayed tumor development in the treated mice was preceded by decreased BrdU nuclear incorporation and inhibited mammary morphogenesis. Molecular analysis indicated that lapatinib inhibited phosphorylation and expression of EGFR, erbB-3, erbB-2, Akt1, and Erk1/2 in premalignant mammary tissues. Also, lapatinib drastically inhibited the phosphorylation and expression of ERα and the transcription of ER target genes in premalignant mammary tissues. We also determined that lapatinib suppressed the stemness of breast cancer cell lines, as evidenced by decreased tumorsphere formation and ALDH+ cell populations. CONCLUSIONS: Taken together, these data demonstrate that brief treatment with EGFR/erbB-2-targeting agents before the onset of tumors may provide lifelong protection from mammary tumors, through the concurrent inhibition of erbB-2 and ER signaling pathways and consequential reprogramming. Our findings support further clinical testing to explore the benefit of shorter lapatinib exposure in the prevention of erbB-2-mediated carcinogenesis. KEYWORDS: Crosstalk; EGFR; ErbB-2/Her2; Estrogen receptor (ER); Lapatinib; MMTV-erbB-2 transgenic mice PMID: 28061785 DOI: 10.1186/s13046-016-0479-8
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