Analysis of mechanisms underlying BRMS1 suppression of metastasis
Analysis of mechanisms underlying BRMS1 suppression of metastasis
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DOI：
10.1023/a:1013124725690
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发表时间：
2001-01-01
影响因子：
4
通讯作者：
Welch, DR
中科院分区：
文献类型：
--
作者：
Samant, RS;Seraj, MJ;Welch, DR
引入正常的、新霉素标记的人类 11 号染色体 (neo11) 可将 MDA-MB-435 人类乳腺癌细胞的转移能力降低 70-90%，而不影响致瘤性。通过比较 MDA-MB-435 和 neo11/435 的差异显示，发现了人类乳腺癌转移抑制基因 BRMS1，该基因定位于染色体 11q13.1-q13.2。将具有 BRMS1 cDNA 的 MDA-MB-435 和 MDA-MB-231 乳腺癌细胞的稳定转染子注射到无胸腺小鼠的乳腺脂肪垫中时，仍会形成逐渐生长的局部侵袭性肿瘤，但对肺部和区域淋巴结的转移潜力显着降低（50-90% 抑制）。为了开始阐明作用机制，我们测量了 BRMS1 扰乱体外模拟的转移级联的各个步骤的能力。与细胞外基质成分（层粘连蛋白、纤连蛋白、IV 型胶原、I 型胶原、Matrigel）的粘附没有观察到一致的差异；体外或体内生长率；基质金属蛋白酶、乙酰肝素酶或侵袭的表达。同样，BRMS1 表达不会上调其他转移抑制因子的表达，例如 NM23、Kai1、KiSS1 或 E-钙粘蛋白。与亲本转染子和仅载体转染子相比，BRMS1 转染子的运动性受到适度抑制（30-60%）。 MDA-MB-435 细胞在软琼脂中的生长能力也下降了 80-89%，但 MDA-MB-231 的下降幅度较小（下降了 13-15%）。此外，BRMS1 的转染和重新表达恢复了人乳腺癌细胞形成功能性同型间隙连接的能力。总的来说，这些数据表明 BRMS1 通过复杂的非典型机制抑制人类乳腺癌的转移。
Introduction of normal, neomycin-tagged human chromosome 11 (neo11) reduces the metastatic capacity of MDA-MB-435 human breast carcinoma cells by 70-90% without affecting tumorigenicity. Differential display comparing MDA-MB-435 and neo11/435 led to the discovery of a human breast carcinoma metastasis suppressor gene, BRMS1, which maps to chromosome 11q13.1-q13.2. Stable transfectants of MDA-MB-435 and MDA-MB-231 breast carcinoma cells with BRMS1 cDNA still form progressively growing, locally invasive tumors when injected in mammary fat pads of athymic mice but exhibit significantly lower metastatic potential (50-90% inhibition) to lungs and regional lymph nodes. To begin elucidating the mechanism(s) of action, we measured the ability of BRMS1 to perturb individual steps of the metastatic cascade modeled in vitro. Consistent differences were not observed for adhesion to extracellular matrix components (laminin, fibronectin, type IV collagen, type I collagen, Matrigel); growth rates in vitro or in vivo; expression of matrix metalloproteinases, heparanase, or invasion. Likewise, BRMS1 expression did not up regulate expression of other metastasis suppressors, such as NM23, Kai1, KiSS1 or E-cadherin. Motility of BRMS1 transfectants was modestly inhibited (30-60%) compared to parental and vector-only transfectants. Ability to grow in soft agar was also decreased in MDA-MB-435 cells by 80-89%, but the decrease for MDA-MB-231 was less (13-15% reduction). Also, transfection and re-expression of BRMS1 restored the ability of human breast carcinoma cells to form functional homotypic gap junctions. Collectively, these data suggest that BRMS1 suppresses metastasis of human breast carcinoma by complex, atypical mechanisms.