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Expression Correlates with Retinoid-induced Growth Inhibition of Human Breast Cancer Cells Regardless of Estrogen Receptor Status
Department of Retinoid Research, Ligand Pharmaceuticals, Inc., San Diego, California 92121 [P. F., R. A. H., E. A. A.], and Retinoid Research Departments of Chemistry [M. T., R. A. S. C.] and Biology [R. A. S. C.], Allergan, Inc., Irvine, California 92715
Retinoic acid receptor (RAR) 
has been shown to play a role in retinoid-induced growth inhibition of human breast cancer cell lines that express the estrogen receptor (ER). The dogma in the field has been that ER-positive breast cancer cell lines respond to retinoid treatment because they express RAR, whereas ER-negative breast cancer cell lines are refractory to retinoid treatment and have been thought to express little or no RAR. We set out to test several ER-negative breast cancer cell lines for expression of RAR protein and responsiveness to retinoids in growth inhibition assays. Of six ER-negative breast cancer cell lines that were tested, one (SK-BR-3) had high levels of RAR protein as measured by ligand-binding immunoprecipitation (
55 fmol/mg protein) and also displayed sensitivity to growth inhibition by retinoids (9-cis-retinoic acid; EC50, 
3 nM). These cells were more sensitive than an ER-positive cell line, T-47D, which expressed 35 fmol RAR/mg total protein (9-cis retinoic acid; EC50, 50–100 nM). Another ER-negative cell line, Hs578T, also expressed RAR (23 fmol/mg) and was sensitive to retinoid-induced growth inhibition, albeit to a lesser extent than SK-BR-3 or T-47D cells. In contrast, the other ER-negative cell lines tested expressed low (<10 fmol/mg) or no detectable levels of RAR protein and also did not respond to retinoids in growth inhibition assays. A RAR agonist displayed 100 times greater potency than a RAR
agonist in growth inhibition of both T-47D and SK-BR-3 cells, suggesting RAR involvement in the process. Furthermore, a RAR antagonist completely abolished the growth inhibition induced by RAR agonist, implying that the activity of the agonists is exerted solely through RAR, not RAR, which is also expressed in both cell lines. Additionally, although retinoid X receptor (RXR) compounds are weakly active in growth inhibition of the RAR-positive cell lines, they markedly increased the growth-inhibitory activity of RAR lingands. RXR compounds also potentiated the action of the antiestrogen 4-hydroxytamoxifen to inhibit the growth of T-47D cells. These findings have clinical ramifications in that patients with ER-negative tumors that are RAR positive may be candidates for retinoid therapy. Additionally, combinations of RXR ligands with RAR lines (especially RAR agonists) and/or antiestrogens may have utility in the treatment of breast cancer.
1 To whom requests for reprints should be addressed, at Department of Retinoid Research, Ligand Pharmaceuticals, Inc., 10255 Science Center Drive, San Diego, CA 92121. Phone: (619) 550-7817; Fax: (619) 550-7805; E-mail: ballegretto@ligand.com.
Received 12/20/96. Accepted 4/28/97.
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