Novel pathway for mammary epithelial cell invasion induced by the helix-loop-helix protein Id-1
Novel pathway for mammary epithelial cell invasion induced by the helix-loop-helix protein Id-1
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DOI：
10.1128/mcb.18.8.4577
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发表时间：
1998-08-01
影响因子：
5.3
通讯作者：
Campisi, J
中科院分区：
文献类型：
--
作者：
Desprez, PY;Lin, CQ;Campisi, J
乳腺上皮细胞在成年期经历生长、侵袭和分化的变化，在妊娠期、哺乳期和复旧期最为显著。虽然乳蛋白的表达途径已经被阐明，但在分子水平上，对正常组织形态发生和侵袭性乳腺癌进化过程中乳腺上皮细胞表型的控制知之甚少。我们开发了一种小鼠乳腺上皮细胞系SCp2，该细胞系在基底膜和产乳激素的作用下抑制生长并在功能上分化。在这些细胞中，基本螺旋-环-螺旋转录因子抑制剂Id-1的表达在分化前下降，组成型Id-1的表达阻断了分化。在这里，我们发现组成性表达Id-1的SCp2细胞缓慢侵入基底膜，但仍然依赖于锚定生长，并且在裸鼠中不形成肿瘤。表达Id-1的细胞分泌一种类似于120 kda明胶酶的明胶酶，从抑制剂研究来看，这种明胶酶似乎是一种金属蛋白酶，并且它是在条件培养基中从这些细胞中检测到的唯一金属蛋白酶。一种无毒抑制剂在体外降低了这种金属蛋白酶的活性，并在培养中抑制了表达id -1细胞的侵袭性表型。这些发现对正常乳腺发育和人类乳腺癌的意义进行了研究。在复旧期间，乳腺表达了一种类似于120 kDa的明胶酶，此时Id-1表达量高，存在广泛的组织重塑。此外，在人乳腺癌细胞中，高水平的Id-1表达和类似于120-kDa明胶酶的活性与分化程度较低和更具侵袭性的表型相关。我们认为，Id-1主要通过诱导一种类似于120 kda明胶酶的表达来控制正常和肿瘤乳腺上皮细胞的侵袭，这种Id-1调节的侵袭性表型可能导致乳腺的退化，并可能导致浸润性乳腺癌的发生。
Mammary epithelial cells undergo changes in growth, invasion, and differentiation throughout much of adulthood, and most strikingly during pregnancy, lactation, and involution. Although the pathways of milk protein expression are being elucidated, little is known, at a molecular level, about control of mammary epithelial cell phenotypes during normal tissue morphogenesis and evolution of aggressive breast cancer. We developed a murine mammary epithelial cell line, SCp2, that arrests growth and functionally differentiates in response to a basement membrane and lactogenic hormones. In these cells, expression of Id-1, an inhibitor of basic helix-loop-helix transcription factors, declines prior to differentiation, and constitutive Id-1 expression blocks differentiation. Here, we show that SCp2 cells that constitutively express Id-1 slowly invade the basement membrane but remain anchorage dependent for growth and do not form tumors in nude mice. Cells expressing Id-1 secreted a similar to 120-kDa gelatinase, From inhibitor studies, this gelatinase appeared to be a metalloproteinase, and it was the only metalloproteinase detectable in conditioned medium from these cells. A nontoxic inhibitor diminished the activity of this metalloproteinase in vitro and repressed the invasive phenotype of Id-1-expressing cells in culture. The implications of these findings for normal mammary-gland development and human breast cancer were investigated. A gelatinase of similar to 120 kDa was expressed by the mammary gland during involution, a time when Id-1 expression is high and there is extensive tissue remodeling. Moreover, high levels of Id-1 expression and the activity of a similar to 120-kDa gelatinase correlated with a less-differentiated and more-aggressive phenotype in human breast cancer cells. We suggest that Id-1 controls invasion by normal and neoplastic mammary epithelial cells, primarily through induction of a similar to 120-kDa gelatinase, This Id-1-regulated invasive phenotype could contribute to involution of the mammary gland and possibly to the development of invasive breast cancer.