Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors.
Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors.
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发表时间：
1993-11
期刊：
影响因子：
11.2
通讯作者：
S. Bacus;A. Gudkov;C. Zelnick;D. Chin;R. Stern;I. Stancovski;E. Peles;N. Ben-Baruch;H. Farbstein;R. Lupu
中科院分区：
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作者：
S. Bacus;A. Gudkov;C. Zelnick;D. Chin;R. Stern;I. Stancovski;E. Peles;N. Ben-Baruch;H. Farbstein;R. Lupu
Neu分化因子（NDF，也称为heregulin）是一种44千道尔顿的糖蛋白，可刺激Neu/HER-2受体的酪氨酸磷酸化，并诱导某些乳腺癌细胞系向生长阻滞和产乳细胞的表型分化。为了确定哪些分子参与了伴随的形态学改变，我们分析了几种细胞骨架和表面分子的表达，发现NDF提高了培养AU-565人腺癌细胞中细胞间粘附分子1 （ICAM-1）的表达。NDF治疗3 ~ 5 d后，ICAM-1蛋白和mRNA水平均升高。γ -干扰素和促瘤磷脂（PMA）也能诱导ICAM-1的表达升高，尽管其动力学不同。蛋白激酶C的下调或calphostin C对其的抑制部分抑制了NDF的作用，提示ICAM-1的诱导可能是由蛋白激酶C介导的。在9个人类乳腺肿瘤中有3个检测到NDF转录本，提示该因子的体外作用可能与乳腺癌有关。通过选择新阳性的人乳腺肿瘤（n = 39），我们发现ICAM-1的表达与浸润性导管癌的组织学特征有显著的相关性（P < 0.001），浸润性导管癌具有显著的原位癌成分。当在体外培养时，这些肿瘤细胞成簇生长，形成圆顶状结构，使人联想到喜剧型原位癌。此外，大多数共表达ICAM-1和Neu的肿瘤患者没有淋巴结受累，不像大多数新阳性但ICAM-1阴性的肿瘤转移到淋巴系统。综上所述，我们的观察结果表明，NDF诱导ICAM-1可能会影响表达new的乳腺肿瘤细胞的形态、分化状态和转移。
Neu differentiation factor (NDF, also called heregulin) is a 44-kilodalton glycoprotein that stimulates tyrosine phosphorylation of the Neu/HER-2 receptor and induces phenotypic differentiation of certain mammary cancer cell lines to growth-arrested and milk-producing cells. To determine which molecules participate in the concomitant morphological alterations, we analyzed the expression of several cytoskeletal and surface molecules and found that NDF elevated the expression of the intercellular adhesion molecule 1 (ICAM-1) in cultured AU-565 human adenocarcinoma cells. The levels of both the protein and the mRNA of ICAM-1 were elevated after 3-5 days of treatment with NDF. Elevated expression of ICAM-1 was induced also by gamma-interferon and by the tumor-promoting phorbol ester (PMA), albeit with different kinetics. Down-regulation of protein kinase C or its inhibition by calphostin C partially inhibited the effect of NDF, implying that the induction of ICAM-1 may be mediated by protein kinase C. NDF transcripts were detectable in 3 of 9 human mammary tumors, suggesting that the in vitro effect of the factor may be relevant to breast cancer. By selecting Neu-positive human mammary tumors (n = 39), we found a significant correlation (P < 0.001) between the expression of ICAM-1 and histological features of invasive ductal carcinoma with a prominent carcinoma in situ component. When cultured in vitro the cells of these tumors grew in clusters and formed domelike structures reminiscent of comedo-type carcinoma in situ. In addition, the majority of patients with tumors that coexpressed ICAM-1 and Neu had no lymph node involvement, unlike most Neu-positive but ICAM-1-negative tumors, which metastasized to the lymphatic system. Taken together, our observations suggest that the induction of ICAM-1 by NDF may affect the morphology, differentiation state, and metastasis of Neu-expressing mammary tumor cells.