IRF-1 promotes apoptosis in p53-damaged basal-type human mammary epithelial cells: a model for early basal-type mammary carcinogenesis.

Published

Journal Article

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.

Full Text

Cited Authors

  • Bowie, ML; Ibarra, C; Seewalt, VL

Published Date

  • January 2008

Published In

Volume / Issue

  • 617 /

Start / End Page

  • 367 - 374

PubMed ID

  • 18497060

Pubmed Central ID

  • 18497060

Electronic International Standard Serial Number (EISSN)

  • 2214-8019

International Standard Serial Number (ISSN)

  • 0065-2598

Digital Object Identifier (DOI)

  • 10.1007/978-0-387-69080-3_35

Language

  • eng