Rao G N, Ney E, Herbert R A
Environmental Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Breast Cancer Res Treat. 1999 Dec;58(3):241-54. doi: 10.1023/a:1006315716713.
Breast cancer is one of the common cancers and is a leading cause of cancer mortality in women. The TG.NK transgenic mouse line on FVB strain background expresses the c-neu oncogene under the control of a MMTV promoter in mammary tissue and appears to be a useful animal model for evaluation of strategies to delay or prevent mammary cancer. Fiber-rich nonpurified diet (NTP-2000) and some retinoid analogues have delayed mammary cancer in the TG.NK model. Four week old hemizygous TG.NK female mice with MMTV/c-neu (erbB2) activated oncogene were fed NTP-2000 diet containing the retinoid analogue 4-hydroxyphenylretinamide (4-HPR) at 7 mmol/kg or the arotinoid Ro 40-8757 at 1.5 and 2.5 mmol/kg for 26 weeks. The 4-HPR at 7 mmol/kg diet delayed the development of palpable tumors up to 24 weeks, but by 26 weeks, the incidence markedly increased and was closer to the NTP-2000 diet control group. However, the 4-HPR diet markedly decreased the average weight of the tumors at 26 weeks with no decrease in multiplicity. The 4-HPR also caused significant increase in liver weights without an effect on body weight. Arotinoid Ro 40-8757 caused marked decrease in the number and branching of mammary ducts, and inhibited mammary tumor development with significant decrease in the incidence, multiplicity, and tumor weights compared to the NTP-2000 diet control. Arotinoid also caused a significant dose-related increase in liver weights without a significant effect on body weights. At the doses tested, the arotinoid but not 4-HPR decreased the circulating levels of IGF-1. However, there was no association between the IGF-1 levels and the size, incidence, or absence of tumors when evaluated for any treatment group or for all mice in the study irrespective of treatment. The oncogene erbB2 (c-neu) and the growth factor EGF expression were more prominent in the small tumors of the mice treated with arotinoid than in the larger tumors of the control group. PCNA staining was observed in areas where there was high erbB2 and EGF staining. The delay in onset of mammary tumors by the above retinoid analogues may be related to the delay in development of mammary glands.
乳腺癌是常见癌症之一，也是女性癌症死亡的主要原因。FVB品系背景的TG.NK转基因小鼠系在乳腺组织中MMTV启动子的控制下表达c-neu癌基因，似乎是评估延缓或预防乳腺癌策略的有用动物模型。富含纤维的非纯化饮食（NTP-2000）和一些类视黄醇类似物在TG.NK模型中延缓了乳腺癌的发生。将四周龄的携带MMTV/c-neu（erbB2）激活癌基因的半合子TG.NK雌性小鼠喂食含7 mmol/kg类视黄醇类似物4-羟基苯基视黄酰胺（4-HPR）或1.5 mmol/kg和2.5 mmol/kg阿维A酯Ro 40-8757的NTP-2000饮食，持续26周。饮食中含7 mmol/kg的4-HPR使可触及肿瘤的发生延迟至24周，但到26周时，发病率显著增加，且更接近NTP-2000饮食对照组。然而，4-HPR饮食在26周时显著降低了肿瘤的平均重量，而肿瘤数量未减少。4-HPR还导致肝脏重量显著增加，而对体重无影响。阿维A酯Ro 40-8757使乳腺导管的数量和分支显著减少，并抑制乳腺肿瘤的发生，与NTP-2000饮食对照组相比，发病率、肿瘤数量和肿瘤重量均显著降低。阿维A酯还导致肝脏重量显著增加且与剂量相关，而对体重无显著影响。在所测试的剂量下，阿维A酯而非4-HPR降低了循环中的IGF-1水平。然而，在评估任何治疗组或研究中的所有小鼠（无论治疗情况如何）时，IGF-1水平与肿瘤大小、发病率或有无肿瘤之间均无关联。在用阿维A酯治疗的小鼠的小肿瘤中，癌基因erbB2（c-neu）和生长因子EGF的表达比对照组的大肿瘤中更明显。在erbB2和EGF染色高的区域观察到PCNA染色。上述类视黄醇类似物使乳腺肿瘤发病延迟可能与乳腺发育延迟有关。
