Retinoids have antiproliferative effects in human
breast cancer cells and share some characteristics with
antiestrogens, although the molecular targets involved have yet to be identified in either case. Using T-47D human
breast cancer cells, we compared the effects of
retinoic acid (RA) and the
antiestrogen ICI 164384 on cell cycle phase distribution and the expression of genes with known functions in cell cycle control. Both RA and
ICI 164384 inhibited cell cycle progression in G1 phase, but the RA effect was delayed by 16 h. This delay in action was also seen with 9-cis RA and other
retinoids. Administration of
17 beta-estradiol abolished the effects of
ICI 164384 but was without effect in RA-treated cells.
Antiestrogen treatment caused a rapid inhibition of c-myc and cyclin D1 gene expression and reduced Cdk2 activity by more than 50% at 24 h. RA, however, did not affect c-myc or cyclin D1 gene expression, nor did it significantly change the
mRNA or
protein levels of
cyclins D3 or E or
cyclin-dependent kinases (CDK) Cdk2 or Cdk4. RA-induced reduction in Cdk2 activity was modest and occurred after %S phase declined, while Cdk4 activity was reduced, coincident with cell cycle changes. However, following either RA or
ICI 164384, there was a reduction in the amount of hyperphosphorylated pRB, first apparent well before cell cycle changes were seen. These data demonstrate that: (a) the mechanisms of action of
antiestrogens and
retinoids are different but converge at pRB; and (b) RA can affect CDK activity without reducing
cyclin or CDK levels.