In recent years, the incidence of breast cancer has been increasing worldwide, and breast cancer is becoming a serious object of public concern. The onset of breast cancer is closely related to the sex hormone estrogen, and estrogen antagonists such as tamoxifen have been used as anti-breast cancer drugs.
During pregnancy, the elevated blood estrogen level induces the proliferation of mammary epithelial cells, leading to the development of the mammary gland in preparation for lactation. The mammary epithelial cells eventually stop proliferation at late stages of pregnancy, impairment of which potentially results in breast tumorigenesis. However, the regulatory mechanisms of mammary epithelial cell proliferation during pregnancy have been unclear.
The absence of tumors in virgin Nrk mutant mice strongly suggests that the tumorigenesis is closely related to the proliferation of mammary epithelial cells during pregnancy. Histopathological examinations showed that this breast tumor is a non-invasive, relatively benign cancer. In addition, the tumor was positive for estrogen receptor alpha (ER alpha) and cell proliferation marker Ki67, and negative for receptor tyrosine kinase HER2/ErbB2, suggesting that it has features like luminal B type breast cancer in humans.
In addition, blood estrogen levels at late stages of pregnancy were found to be about two times higher in Nrk mutant mice than in wild-type mice, suggesting that Nrk is also involved in the regulation of synthesis or secretion of estrogen. In Nrk mutant mice, therefore, mammary tumorigenesis was proposed to be triggered by a combination of dysregulation of proliferation in mammary epithelial cells and excessive blood estrogen.