Estradiol induces cell proliferation in MCF-7 mammospheres through HER2/COX-2

Cluster of differentiation (CD)44(+)/CD24(-) breast cancer cells have stem cell-like characteristics and are potent initiators of tumorigenesis. Mammosphere cells can partially initiate breast tumorigenesis by inducing estradiol (E2)-dependent breast cancer cells. However, the mechanisms by which E2 mediates cancer formation in MCF-7 mammosphere (MS) cells have remained elusive. In the present study, MS cells were isolated by sphere culture. It was possible to maintain these MS cells in culture for long periods of time, while retaining the CD44(+)/CD24(-) stem cell marker status. The CD44(+)/CD24(-) status was confirmed by flow cytometry. Furthermore, the stem-cell markers Musashi-1, cytokeratin (CK)7 and CK19 were identified by immunofluorescence microscopy. It was revealed that treatment of MS cells with E2 increased the expression of CD44, whereas decreased the expression of CD24 on MS cells. In addition, treatment with E2 increased colony formation by MS cells. E2 also induced cyclooxygenase-2 (COX-2) expression in MS cells, which promoted their proliferation through the estrogen receptor/human epidermal growth factor receptor 2 (HER2)/mitogen-activated protein kinase/phosphoinositide-3 kinase signaling pathway. The results suggested a tumorigenic mechanism by which E2 promotes tumor cell proliferation via HER2/COX-2 signaling. The present study provided evidence for the molecular impact of E2 on breast tumorigenesis, and suggested possible strategies for preventing and treating human breast cancer.