Gupta V, Carey J L, Kawakubo H, Muzikansky A, Green J E, Donahoe P K, MacLaughlin D T, Maheswaran S
Department of Surgical Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3219-24. doi: 10.1073/pnas.0409709102. Epub 2005 Feb 22.
Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro. To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P=0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P=0.029). Analysis of proliferating cell nuclear antigen (PCNA) expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and was not caused by a decline in T antigen expression. The effect of MIS on tumor growth was also evaluated on xenografted human breast cancer cell line MDA-MB-468, which is estrogen receptor- and retinoblastoma-negative and expresses mutant p53, and thus complements the C3(1)Tag mouse mammary tumors that do not express estrogen receptor and have functional inactivation of retinoblastoma and p53. In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared with vehicle-treated controls (P=0.004). These results suggest that MIS can suppress the growth of mammary tumors in vivo.
苗勒管抑制物质（MIS）在体外可抑制乳腺癌细胞的生长。为了将MIS的应用扩展至乳腺癌治疗，有必要在体内测试乳腺肿瘤生长对MIS的反应性。在C3(1)T抗原小鼠模型中出现的乳腺肿瘤表达了II型MIS受体，且MIS在体外可抑制肿瘤来源细胞的生长。与用赋形剂处理的小鼠相比，给小鼠施用MIS后可触及的乳腺肿瘤数量较少（P = 0.048），且MIS处理组的平均乳腺肿瘤重量与对照组相比显著降低（P = 0.029）。对肿瘤中增殖细胞核抗原（PCNA）表达和半胱天冬酶-3裂解的分析显示，暴露于MIS分别与增殖减少和凋亡增加相关，且并非由T抗原表达下降所致。还在异种移植的人乳腺癌细胞系MDA-MB-468上评估了MIS对肿瘤生长的影响，该细胞系雌激素受体和视网膜母细胞瘤均为阴性且表达突变型p53，因此补充了不表达雌激素受体且视网膜母细胞瘤和p53功能失活的C3(1)Tag小鼠乳腺肿瘤。与在转基因小鼠中观察到的结果一致，与用赋形剂处理的对照组相比，MIS降低了严重联合免疫缺陷小鼠中MDA-MB-468肿瘤的生长速率和平均肿瘤体积的增加幅度（P = 0.004）。这些结果表明，MIS可在体内抑制乳腺肿瘤的生长。
