IRF-1 promotes apoptosis in p53-damaged basal-type human mammary epithelial cells: a model for early basal-type mammary carcinogenesis.
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 (Tam) and three-dimensional prepared extracellular matrix culture (3-D rECM) induce apoptosis in HMEC cells with acute loss of p53 [*p53(-) HMECs] through induction of interferon regulatory factor-1 (IRF-1). Tam 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 Tam- 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.
Bowie
Michelle L
ML
Duke University Cancer Center, Durham, NC, USA.
Ibarra
Catherine
C
Seewalt
Victoria L
VL
D017209:Apoptosis / Q000502:physiology*; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000502:physiology*; D008954:Models, Biological; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D020169:Caspases