Gao Dongcheng, Liu Jianhua, Yuan Jingping, Wu Juan, Kuang Xinwen, Kong Deguang, Zheng Weijie, Wang Guannan, Sukumar Saraswati, Tu Yi, Chen Chuang, Sun Shengrong
Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China.
Ann Transl Med. 2021 Apr;9(7):576. doi: 10.21037/atm-21-1540.
Chemically induced animal models of breast cancer (BC) using N-methyl-N-nitrosourea (MNU) have been widely used in preclinical research. The conventional approach entails intraperitoneal (i.p) or intravenous injection of a carcinogen, leading to tumor induction at unpredictable locations. This study aimed to establish a modified MNU-induced rat mammary tumor model using intraductal (i.duc) administration and to evaluate its biological behavior, morphology, and response to chemotherapy drugs.
In a pilot experiment, female Sprague-Dawley (SD) rats were injected with either i.duc MNU or vehicle to test the feasibility of this approach. We explored the appropriate dosage for stable tumor formation in pubescent female SD rats by testing a single i.duc dose of MNU (0.5, 1.0 and 2.0 mg) or vehicle.
An i.duc injection of 20 µL (1 mg/per duct) MNU in the fourth rat mammary gland induced stable carcinomas . Immunohistochemical (IHC) analysis showed positive expression of estrogen receptor (ER), negative expression of human epidermal growth factor receptor 2 (Her-2), and low expression of Ki-67. Histopathology revealed atypical hyperplasia in the mammary gland 4 weeks after carcinogen injection, developing into carcinoma 5-6 weeks after treatment, with loss of α-SMA and calponin expressions during tumor progression. Albumin-bound paclitaxel (nab-PTX) was injected i.duc and intravenously (i.v) 5 weeks after administration of MNU. The tumor growth rate of the nab-PTX i.duc-treated group was lower than in the i.v and control groups. The number of TUNEL-positive apoptotic cells was significantly higher in the nab-PTX i.duc-treated group.
Using i.duc MNU (20 µL, 1 mg) to establish a rat mammary tumor model resulted in a predictable location in the rat mammary gland and exhibited better consistency; i.duc administration of nab-PTX permitted a smaller drug dose, but produced a better drug response, than i.v injection.
使用N-甲基-N-亚硝基脲（MNU）化学诱导的乳腺癌动物模型已广泛用于临床前研究。传统方法是通过腹腔内（i.p）或静脉内注射致癌物，导致在不可预测的部位诱发肿瘤。本研究旨在建立一种使用导管内（i.duc）给药的改良MNU诱导大鼠乳腺肿瘤模型，并评估其生物学行为、形态学以及对化疗药物的反应。
在一项预实验中，给雌性斯普拉格-道利（SD）大鼠注射导管内MNU或赋形剂，以测试该方法的可行性。通过测试单剂量导管内注射MNU（0.5、1.0和2.0毫克）或赋形剂，探索青春期雌性SD大鼠稳定形成肿瘤的合适剂量。
在第四乳腺导管内注射20微升（每导管1毫克）MNU可诱导稳定的癌。免疫组织化学（IHC）分析显示雌激素受体（ER）阳性表达、人表皮生长因子受体2（Her-2）阴性表达以及Ki-67低表达。组织病理学显示，致癌物注射后4周乳腺出现非典型增生，治疗后5-6周发展为癌，肿瘤进展过程中α-SMA和钙调蛋白表达缺失。在给予MNU 5周后，导管内和静脉内（i.v）注射白蛋白结合型紫杉醇（nab-PTX）。nab-PTX导管内治疗组的肿瘤生长率低于静脉内治疗组和对照组。nab-PTX导管内治疗组中TUNEL阳性凋亡细胞数量显著更高。
使用导管内MNU（20微升，1毫克）建立大鼠乳腺肿瘤模型，可在大鼠乳腺中获得可预测的部位，并表现出更好的一致性；与静脉内注射相比，导管内给予nab-PTX允许使用更小的药物剂量，但产生更好的药物反应。
