INTERLEUKIN-4 INHIBITS GROWTH AND INDUCES APOPTOSIS IN HUMAN BREAST-CANCER CELLS

Interleukin-4 (IL-4) is a pleiotropic cytokine produced by mast cells and T lymphocytes that promotes proliferation and immunoglobulin class -switching in B cells. IL-4 receptors (IL-4Rs) are also expressed by n onhematopoietic cells as well as some tumor cells. Unlike its mitogeni c effect on B cells, IL-4 inhibits the growth of some cancer cells bl vitro. In this study, we show that IL-4R is expressed by breast and ov arian cancer cell lines. Furthermore, anchorage-dependent and -indepen dent growth of breast cancer cell lines MCF-7 and MDA-MB-231 is inhibi ted by IL-4 treatment, and this effect requires IL-4R. Interestingly, IL-4 only inhibited proliferating breast cancer cells and had no effec t on basal, unstimulated growth. We therefore characterized the effect of IL-4 on breast cancer cell growth stimulated by either estradiol o r insulin-like growth factor I (IGF-I). In both anchorage-dependent an d -independent growth assays, IL-4 inhibited estradiol-stimulated grow th, The antiestrogen effect of IL-4 was not due to IL-4 interference w ith the estrogen receptor, because IL-4 did not interfere with estroge n receptor-mediated reporter gene transactivation. In contrast, IL-4 h ad no effect on IGF-I-stimulated proliferation. Because IGF-I is known to inhibit programmed cell death, we examined apoptosis as a possible mechanism of IL-4 action. We established that IL-4 induced apoptosis in breast cancer cells by five independent criteria: (a) morphological indicators including pyknotic nuclei and cytoplasmic condensation; (b ) DNA fragmentation; (c) the formation of DNA laddering; (d) the cleav age of poly(ADP-ribose) polymerase; and (e) the presence of cells with sub-G(1) DNA content. IL-4 increased the percentage of apoptotic cell s in MCF-7 and MDA-MB-231 cells 6.0- and 6.7-fold over that of the con trol, respectively. Finally, the addition of IGF-I reversed IL-4-induc ed apoptosis, suggesting that the mechanism of IL-4-induced growth inh ibition in human breast cancer cells is the induction of programmed ce ll death.