IRF-1 Promotes Apoptosis in p53-damaged Basal-type Human Mammary Epithelial Cells: A Model for Early Basal-type Mammary Carcinogenesis

摘要

Mammary gland homeostasis is regulated by both endogenous and exogenous signals, creating a balance between proliferation and apoptosis. It is thought that breast cancer develops from the acquisition of multiple genetic changes. The function of tumor suppressor p53 is fequently lost in cancers; however, not all cells that lose p53 progress to become invasive cancer. We have developed a model of early mammary carcinogenesis to investigate some of the internal and external signaling pathways that target the elimination ot normal basal-type human mammary epithelial cells (HMECs) that acutely acquire p53-damage. Here, we show that both tamoxifen (Tarn) and three-dimensional prepared extracellular matrix culture (3-D rECM) induce apoptosis in HMEC cells with acute loss of p53 [p53(-)^sHMECs] through induction of interferon regulatory factor-1 (IRF-1). Tarn and rECM signaling in p53(~) HMECs (1) promotes the recruitment of a STAT1/ CBP complex to the IRF-1 promoter, (2) upregulates IRF-1, (3) activates caspase-1 and -3, and (4) induces apoptosis. Suppression of IRF-1 with siRNA oligos inhibited both Tarn- and rECM-induced apoptosis. These observations demonstrate that IRF-1 plays a critical role in eliminating p53-damaged cells, and may play a more global role in mammary gland homeostasis.