Jackson-Fisher Amy J, Bellinger Gary, Breindel Jerrica L, Tavassoli Fatteneh A, Booth Carmen J, Duong James K, Stern David F
Department of Pathology, Yale School of Medicine, New Haven, CT 06520-8023, USA.
Breast Cancer Res. 2008;10(6):R96. doi: 10.1186/bcr2198. Epub 2008 Nov 18.
The receptor ErbB3/HER3 is often over-expressed in human breast cancers, frequently in conjunction with over-expression of the proto-oncogene ERBB2/HER2/NEU. Although the prognostic/predictive value of ErbB3 expression in breast cancer is unclear, ErbB3 is known to contribute to therapeutic resistance. Understanding ErbB3 functions in the normal mammary gland will help to explain its role in cancer etiology and as a modulator of signaling responses to the mammary oncogene ERBB2.
To investigate the roles of ErbB3 in mouse mammary gland development, we transplanted mammary buds from ErbB3-/- embryos into the cleared mammary fat pads of wild-type immunocompromised mice. Effects on ductal outgrowth were analyzed at 4 weeks, 7 weeks and 20 weeks after transplantation for total ductal outgrowth, branch density, and number and area of terminal end buds. Sections of glands containing terminal end buds were analyzed for number and epithelial area of terminal end buds. Terminal end buds were also analyzed for presence of mitotic figures, apoptotic figures, BrdU incorporation, and expression of E-cadherin, P-cadherin, alpha-smooth muscle actin, and cleaved caspase-3.
The mammary ductal trees developed from ErbB3-/- buds only partly filled the mammary fat pad. In contrast to similar experiments with ErbB2-/- mammary buds, this phenotype was maintained through adulthood, pregnancy, and parturition. In addition, and in contrast to similar work with ErbB4-/- mammary buds, lobuloalveolar development of ErbB3-/- transplanted glands was normal. The ErbB3-/- mammary outgrowth defect was associated with a decrease in the size of the terminal end buds, and with increases in branch density, in the number of terminal end buds, and in the number of luminal spaces. Proliferation rates were not affected by the lack of ErbB3, but there was an increase in apoptosis in ErbB3-/- terminal end buds.
Endogenous ErbB3 regulates morphogenesis of mammary epithelium.
受体ErbB3/HER3在人类乳腺癌中常过度表达，且常与原癌基因ERBB2/HER2/NEU的过度表达同时出现。尽管ErbB3在乳腺癌中的预后/预测价值尚不清楚，但已知其会导致治疗抵抗。了解ErbB3在正常乳腺中的功能将有助于解释其在癌症病因中的作用，以及作为乳腺癌基因ERBB2信号反应调节剂的作用。
为了研究ErbB3在小鼠乳腺发育中的作用，我们将来自ErbB3基因敲除胚胎的乳腺芽移植到野生型免疫缺陷小鼠清除后的乳腺脂肪垫中。在移植后4周、7周和20周分析对导管生长的影响，包括总导管生长、分支密度、末端芽的数量和面积。对含有末端芽的腺体切片分析末端芽的数量和上皮面积。还分析了末端芽的有丝分裂图、凋亡图、BrdU掺入情况，以及E-钙黏蛋白、P-钙黏蛋白、α-平滑肌肌动蛋白和裂解的半胱天冬酶-3的表达。
由ErbB3基因敲除芽发育而来的乳腺导管树仅部分填充乳腺脂肪垫。与用ErbB2基因敲除乳腺芽进行的类似实验不同，这种表型在成年期、孕期和分娩期均保持。此外，与用ErbB4基因敲除乳腺芽进行的类似研究不同，ErbB3基因敲除移植腺体的小叶腺泡发育正常。ErbB3基因敲除的乳腺生长缺陷与末端芽大小减小、分支密度增加、末端芽数量增加以及管腔空间数量增加有关。增殖率不受ErbB3缺失的影响，但ErbB3基因敲除的末端芽中凋亡增加。
内源性ErbB3调节乳腺上皮的形态发生。
