Prevention of Breast Cancer Tumor Growth by Retinoic Acid

Institution: The Burnham Institute for Medical Research
Investigator(s): Yi Liu, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1FB-0309 Award: $10,310
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1995)
A substantial body of data has demonstrated that retinoids, the natural and synthetic vitamin A derivatives, are effective in inhibiting the proliferation of breast cancer cells. Currently, retinoids are being used in clinical trials against breast cancer. However, the anti-proliferative effect of retinoids is most frequently observed in hormone-dependent human breast cancer cells, and this effect appears to diminish in hormone-independent cells during the progression of breast cancer. The molecular mechanism of growth inhibition by retinoids is currently unclear. In the proposed project, the molecular mechanism of the retinoid growth inhibitory effect will be studied. Results from this study may provide a molecular basis for developing more effective and potent retinoids in the prevention of breast cancer, and may also lead to early detection and valuable diagnostic markers for breast cancer.

The effect of retinoids is controlled by nuclear retinoid receptors (proteins which bind to retinoids and change the production of other proteins). Recently we have found that retinoic acid receptor b, a nuclear retinoid receptor, is the only retinoid receptor whose expression is induced by retinoic acid in hormone-dependent, but not in hormone-independent cells, which correlates well with the observed retinoic acid growth inhibitory effect. Preliminary studies have further shown that the introduction of retinoic acid receptor b into a hormone-independent breast cancer cell line that lacks the production of retinoic acid receptor b restores the retinoic acid growth inhibitory effect. Based on these preliminary results, the proposed project will study the necessity of retinoic acid receptor b for retinoic acid growth inhibition in breast cancer cells. Efforts will be undertaken to study the retinoic acid receptor b production and the recovery of retinoic acid growth inhibition in different hormone-independent cells. Furthermore, retinoic acid receptor b selective retinoids will be used to specifically activate and counteract retinoic acid receptor b activity in both hormone-dependent cells and retinoic acid receptor b producing hormone-independent cells. Retinoic acid receptor b will also be eliminated from hormone-dependent cells using molecular biology techniques. Our preliminary studies have also demonstrated that cancer cell death can be induced by retinoic acid only in hormone-dependent cells. Therefore, the molecular mechanism by which retinoic acid receptor b induces cancer cell death and how the process contributes to the anti-cancer effect of retinoic acid will be studied.


Final Report (1996)
Retinoids, the natural and synthetic vitamin A derivatives, are effective in inhibiting the proliferation of breast cancer cells. However, the anti-proliferative effect of retinoids is most frequently observed in hormone-dependent human breast cancer cells, and is diminished in hormone-independent cells during the progression of breast cancer. The objective of this project was to understand the molecular mechanism of the growth inhibitory effect of retinoids in breast cancer.

The effect of retinoids is controlled by nuclear retinoid receptors. Recently we have found that retinoic acid receptor b (RAR b), a nuclear retinoid receptor, is the only retinoid receptor whose expression is induced by retinoic acid (RA) in hormone-dependent, but not hormone-independent cells, which correlates well with the observed RA growth inhibitory effect. Further studies have showed that introduction of RAR b into a hormone-independent breast cancer cell line that lacks the production of RAR b restores the RA growth inhibitory effect. When the activity of RAR b was reduced by a specific retinoid and the production of RAR b was eliminated in a hormone-dependent breast cancer cells, the RA growth inhibitory effect is dramatically decreased. We have also found that introduction of retinoic acid receptor b, another nuclear retinoid receptors, has the same RA growth inhibitory effect through the induction of RAR b. These data have shown that RAR b is the nuclear retinoid receptor that involves in RA growth inhibition in human breast cancer cells. Further studies revealed that cancer cell death contributes to this RA growth inhibition. This study has provided the molecular mechanism on RA growth inhibitory effect in hormone-dependent breast cancer that can direct the synthesis of RAR b specific retinoids in preventing and treating of breast cancer.