All-trans retinoic acid inhibits the growth of breast cancer cells by up-regulating ICAM-1 expression

All-trans retinoic acid (ATRA) is currently used in clinical trials for bre ast cancer, in virtue of its ability to inhibit cell growth and to promote cell differentiation. Elucidation of the molecular mechanism(s) underlying the pleiotropic pharmacological activity of ATRA is of fundamental relevanc e for an effective use of the compound in clinics. This paper reports on th e effects of ATRA treatment on the cell surface expression of a panel of ad hesion molecules known to regulate the interactions between the effecters o f the immune system and tumor targets. Results indicate that breast cancer (BC) cell lines exposed to ATRA selectively up-modulate the surface express ion of ICAM-1/CD54, a molecule regulating cell/cell contacts. Such effect c ould be reproduced in all the BC cell lines analyzed, independently of thei r hormone receptor status, indicating that estrogens and progesterone are i rrelevant in this process. The regulatory effects on ICAM-1 expression are time- and dose-dependent and reversible. Moreover, other differentiating an d proliferating agents comparatively tested, e.g. dimethyl sulfoxide, estra diol or dexamethas one, are ineffective, indicating that ICAM-1 up-modulati on is uniquely featured by ATRA. A second observation is that ATRA treated cells are, only apparently, less sensitive to lysis by lymphocytes activate d by IL-2, as determined by means of a standard Cr-51 release assay. In fac t, notwithstanding this effect, a marked reduction in the ability to form c olonies was highlighted in ATRA treated versus control lines after incubati on with LAK. Finally, the clonogenic killing effect could be reversed using anti-CDW mAbs as blocking tools, indicating that ICAM-1 plays a key role i n the phenomena.