Sebastian J, Richards R G, Walker M P, Wiesen J F, Werb Z, Derynck R, Hom Y K, Cunha G R, DiAugustine R P
Hormones and Cancer Group, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Cell Growth Differ. 1998 Sep;9(9):777-85.
The hormonal stimulation of mammary gland morphogenesis is believed to occur through growth factor receptor signaling pathways. To determine the importance of the epidermal growth factor receptor (EGFR) pathway, we examined extracts of inguinal mammary glands from prepubertal and pubertal mice for tyrosine-phosphorylated EGFR and other erbB receptors. Tyrosine phosphorylation of both EGFR and erbB-2 was detected in normal female BALB/c mice at 5-6 weeks of age, but not during the prepubertal stage, e.g., 24 days of age. Treatment of mice with estradiol or epidermal growth factor also stimulated the formation of mammary EGFR/erbB-2 phosphotyrosine. Waved-2 mice, which have impaired EGFR kinase activity, exhibited less mammary development than did wild-type (wt) mice when both were evaluated at 36 days of age. Because EGFR knockout (KO) mice die shortly after birth, glands from the newborns were implanted under the renal capsules of female nude mice. Under these conditions, extensive ductal growth was observed in mammary glands from wt animals; in contrast, glands from EGFR KO mice failed to grow beyond rudimentary structures. Tissue recombinants revealed that the wt fat pad supported the morphogenesis of EGFR KO epithelium, whereas the EGFR KO fat pad did not. Taken together, these data suggest that EGFR is essential for morphogenesis of the mammary ducts and functions during this period of mammary development as a heterodimer with erbB-2 in the mammary stroma.
乳腺形态发生的激素刺激被认为是通过生长因子受体信号通路发生的。为了确定表皮生长因子受体（EGFR）通路的重要性，我们检测了青春期前和青春期小鼠腹股沟乳腺提取物中酪氨酸磷酸化的EGFR和其他erbB受体。在5-6周龄的正常雌性BALB/c小鼠中检测到EGFR和erbB-2的酪氨酸磷酸化，但在青春期前阶段，如24日龄时未检测到。用雌二醇或表皮生长因子处理小鼠也刺激了乳腺EGFR/erbB-2磷酸酪氨酸的形成。EGFR激酶活性受损的Waved-2小鼠在36日龄时的乳腺发育比野生型（wt）小鼠少。由于EGFR基因敲除（KO）小鼠出生后不久就死亡，将新生小鼠的腺体植入雌性裸鼠的肾包膜下。在这些条件下，观察到wt动物乳腺中有广泛的导管生长；相比之下，EGFR KO小鼠的腺体未能生长到初级结构以外。组织重组显示，wt脂肪垫支持EGFR KO上皮的形态发生，而EGFR KO脂肪垫则不支持。综上所述，这些数据表明EGFR对于乳腺导管的形态发生至关重要，并且在乳腺发育的这一时期作为与乳腺基质中的erbB-2的异二聚体发挥作用。
