Pretreatment with vitamin A inhibits transforming growth factor alpha stimulation of human mammary carcinoma cells

Vitamin A or retinol is an important agent in the normal differentiation and growth of cells. Retinol is an effective inhibitor of the growth of many transformed cells in vitro and in vivo but its mechanism of action is unclear. Transforming growth factor alpha (TGFα) is a known mitogen. We examined the effect of retinol treatment on TGFα stimulation of two human mammary carcinoma cell lines, one which is growth inhibited by retinol and one which is not. Pretreatment of both cell lines for 48 hours with retinol resulted in inhibition of TGFα stimulation of growth. In the T47D cell line the mechanism was not related to an effect on the cellular content of TGFα, epidermal growth factor (EGF) receptor protein, EGF receptor mRNA, or on the binding of TGFα to the EGF receptor. However, TGFα‐induced stimulation of the EGF receptor substrate, phospholipase C‐γ1, was abrogated in the T47D cell line with retinol pretreatment. In the MDA‐MB‐468 cell line, pretreatment with retinol resulted in a decrease in tyrosine phosphorylation of the EGF receptor. These results suggest that pretreatment with retinol decreases cellular proliferation seen with TGFα treatment by altering phospholipase C‐γ1 response and/or EGF receptor tyrosine kinase activity. Alteration of phospholipase C‐γ1 activity does not appear to be responsible for the inhibition of cell growth seen in the absence of TGFα stimulation. © 1993 Wiley‐Liss, Inc.