Jones Robert A, Watson Katrina L, Campbell Craig I, Moorehead Roger A
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, Toronto, Ontario, Canada.
PLoS One. 2014 Sep 26;9(9):e108781. doi: 10.1371/journal.pone.0108781. eCollection 2014.
Although breast cancer typically develops in women over the age of 40, it remains unclear when breast cancer initiating events occur or whether the mammary gland is particularly susceptible to oncogenic transformation at a particular developmental stage. Using MTB-IGFIR transgenic mice that overexpress type I insulin-like growth factor receptor (IGF-IR) in a doxycycline-inducible manner, mammary tumorigenesis was initiated at different developmental stages. Tumor multiplicity was significantly increased while tumor latency was significantly decreased when the IGF-IR transgene was expressed during pubertal development compared to post-pubertal transgene expression. Moreover, metastatic spread of mammary tumors to the lungs was approximately twice as likely when IGF-IR was overexpressed in pubertal mice compared to post-pubertal mice. In addition, engraftment of pubertal MTB-IGFIR mammary tissue into cleared mammary fat pads of pubertal hosts produced tumors more frequently and faster than engraftment into adult hosts. These experiments show that the mammary microenvironment created during puberty renders mammary epithelial cells particularly susceptible to transformation.
尽管乳腺癌通常在40岁以上的女性中发生，但乳腺癌起始事件何时发生，或者乳腺在特定发育阶段是否特别容易发生致癌转化，目前仍不清楚。利用以强力霉素诱导方式过表达I型胰岛素样生长因子受体（IGF-IR）的MTB-IGFIR转基因小鼠，在不同发育阶段启动乳腺肿瘤发生。与青春期后转基因表达相比，当IGF-IR转基因在青春期发育期间表达时，肿瘤多样性显著增加，而肿瘤潜伏期显著缩短。此外，与青春期后小鼠相比，青春期小鼠中IGF-IR过表达时，乳腺肿瘤转移至肺部的可能性约为两倍。此外，将青春期MTB-IGFIR乳腺组织植入青春期宿主清除后的乳腺脂肪垫中，比植入成年宿主更频繁、更快地产生肿瘤。这些实验表明，青春期形成的乳腺微环境使乳腺上皮细胞特别容易发生转化。
