Abstract P1-12-14: Retinoic acid sensitizes triple-negative breast cancer cells to tamoxifen treatment

Abstract

Tamoxifen, an estrogen receptor (ER) antagonist, is often used as an adjuvant endocrine therapy in the successful treatment of ER+ breast tumors. Tumors that lack ER, progesterone receptor (PR) and HER2 expression (i.e. triple-negative breast cancers) cannot be treated with adjuvant endocrine therapies, like tamoxifen, and are often more aggressive. Inducing ER expression is a potential strategy for sensitization of triple-negative breast cancers to adjuvant endocrine therapies. Given recent evidence suggesting cross-talk between the retinoic acid (RA) and estrogen signaling pathways, we investigated if RA induces expression of ER in triple-negative breast cancer cells. We hypothesize that this would lead to sensitization of the cells to tamoxifen treatment. Quantitative PCR of mRNA isolated from triple-negative MDA-MB-231 cells treated with RA and estradiol had increased ER transcript levels. Furthermore, treatment with estradiol and RA synergistically induced increased expression of RA-inducible genes. In cell proliferation studies, neither RA nor estradiol treatment alone significantly altered the growth of MDA-MB-231 cells; however, when treated with both estradiol and RA together, the growth of the cells increased significantly. This suggests that the RA-mediated increase in ER expression sensitizes MDA-MB-231 cells to estradiol-induced cell growth. Next, we investigated whether the increased ER expression sensitized MDA-MB-231 cells to tamoxifen treatment. Tamoxifen did not decrease the growth of MDA-MB-231 cells; however, when applied in combination with both estradiol and RA, tamoxifen significantly reduced MDA-MB-231 proliferation. Furthermore, tamoxifen treatment reduced the synergistic effects of estradiol/RA on RA-inducible gene expression. Together, these results suggest that the use of RA in combination with tamoxifen warrants further investigation as a potential treatment for triple-negative breast cancers. The success of the combination treatment of tamoxifen and RA in the reduction of triple-negative breast cancer cell tumor xenografts will provide further justification for this strategy in the treatment of triple-negative breast cancers.

Citation Format: Krysta M Coyle, Cheryl A Dean, Diana B Jo, Margaret Thomas, Mohammad Sultan, Paola Marcato. Retinoic acid sensitizes triple-negative breast cancer cells to tamoxifen treatment [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-14.