Lindvall Charlotta, Zylstra Cassandra R, Evans Nicole, West Richard A, Dykema Karl, Furge Kyle A, Williams Bart O
Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
PLoS One. 2009 Jun 5;4(6):e5813. doi: 10.1371/journal.pone.0005813.
Canonical Wnt signals are transduced through a Frizzled receptor and either the LRP5 or LRP6 co-receptor; such signals play central roles during development and in disease. We have previously shown that Lrp5 is required for ductal stem cell activity and that loss of Lrp5 delays normal mammary development and Wnt1-induced tumorigenesis. Here we show that canonical Wnt signals through the Lrp6 co-receptor are also required for normal mouse mammary gland development. Loss of Lrp6 compromises Wnt/beta-catenin signaling and interferes with mammary placode, fat pad, and branching development during embryogenesis. Heterozygosity for an inactivating mutation in Lrp6 is associated with a reduced number of terminal end buds and branches during postnatal development. While Lrp6 is expressed in both the basal and luminal mammary epithelium during embryogenesis, Lrp6 expression later becomes restricted to cells residing in the basal epithelial layer. Interestingly, these cells also express mammary stem cell markers. In humans, increased Lrp6 expression is associated with basal-like breast cancer. Taken together, our results suggest both overlapping and specific functions for Lrp5 and Lrp6 in the mammary gland.
经典Wnt信号通过卷曲蛋白受体以及低密度脂蛋白受体相关蛋白5（LRP5）或低密度脂蛋白受体相关蛋白6（LRP6）共受体进行转导；此类信号在发育过程和疾病中发挥核心作用。我们之前已经表明，LRP5是导管干细胞活性所必需的，并且LRP5的缺失会延迟正常乳腺发育以及Wnt1诱导的肿瘤发生。在此我们表明，通过LRP6共受体的经典Wnt信号对于正常小鼠乳腺发育也是必需的。LRP6的缺失会损害Wnt/β-连环蛋白信号传导，并在胚胎发生过程中干扰乳腺基板、脂肪垫和分支发育。LRP6失活突变的杂合性与出生后发育过程中端末终芽和分支数量减少有关。虽然LRP6在胚胎发生过程中在乳腺基底上皮和管腔上皮中均有表达，但LRP6的表达后来局限于位于基底上皮层的细胞。有趣的是，这些细胞也表达乳腺干细胞标志物。在人类中，LRP6表达增加与基底样乳腺癌相关。综上所述，我们的结果表明LRP5和LRP6在乳腺中具有重叠和特定的功能。
