Sun Youping, Strizzi Luigi, Raafat Ahmed, Hirota Morihisa, Bianco Caterina, Feigenbaum Lionel, Kenney Nicholas, Wechselberger Christian, Callahan Robert, Salomon David S
Tumor Growth Factor Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, MD 20892, USA.
Am J Pathol. 2005 Aug;167(2):585-97. doi: 10.1016/S0002-9440(10)63000-3.
Overexpression of Cripto-1 has been reported in several types of human cancers including breast cancer. To investigate the role of human Cripto-1 (CR-1) in mammary gland development and tumorigenesis, we developed transgenic mice that express the human CR-1 transgene under the regulation of the whey acidic protein (WAP) promoter in the FVB/N mouse background. The CR-1 transgene was detected in the mammary gland of 15-week-old virgin WAP-CR-1 female mice that eventually developed hyperplastic lesions. From mid-pregnancy to early lactation, mammary lobulo-alveolar structures in WAP-CR-1 mice were less differentiated and delayed in their development due to decreased cell proliferation as compared to FVB/N mice. Early involution, due to increased apoptosis, was observed in the mammary glands of WAP-CR-1 mice. Higher levels of phosphorylated AKT and MAPK were detected in mammary glands of multiparous WAP-CR-1 mice as compared to multiparous FVB/N mice suggesting increased cell proliferation and survival of the transgenic mammary gland. In addition, more than half (15 of 29) of the WAP-CR-1 multiparous female mice developed multifocal mammary tumors of mixed histological subtypes. These results demonstrate that overexpression of CR-1 during pregnancy and lactation can lead to alterations in mammary gland development and to production of mammary tumors in multiparous mice.
已有报道称，Cripto-1在包括乳腺癌在内的多种人类癌症中过表达。为了研究人类Cripto-1（CR-1）在乳腺发育和肿瘤发生中的作用，我们构建了转基因小鼠，其在FVB/N小鼠背景下，在乳清酸性蛋白（WAP）启动子的调控下表达人类CR-1转基因。在最终发生增生性病变的15周龄未孕WAP-CR-1雌性小鼠的乳腺中检测到了CR-1转基因。从妊娠中期到泌乳早期，与FVB/N小鼠相比，WAP-CR-1小鼠的乳腺小叶-腺泡结构分化较差且发育延迟，这是由于细胞增殖减少所致。在WAP-CR-1小鼠的乳腺中观察到由于细胞凋亡增加导致的早期 involution。与经产FVB/N小鼠相比，在经产WAP-CR-1小鼠的乳腺中检测到更高水平的磷酸化AKT和MAPK，这表明转基因乳腺的细胞增殖和存活增加。此外，超过一半（29只中的15只）的WAP-CR-1经产雌性小鼠发生了组织学亚型混合的多灶性乳腺肿瘤。这些结果表明，妊娠和哺乳期CR-1的过表达可导致乳腺发育改变，并在经产小鼠中产生乳腺肿瘤。
