Antitumor activities of natural and synthetic retinoids in 2D and 3D human breast cancer models -

Abstract

Breast cancer is the most common malignancy among women and the second cause of cancer-related death worldwide. Despite recent advances in the use of chemotherapy in breast cancer management, achieving complete remission in aggressive and metastatic cancer patients remains a challenge and urges for the development of effective and safer therapies. Retinoids, including vitamin A derivatives and synthetic analogs, regulate cellular proliferation, differentiation, and cell death, and have shown potent chemotherapeutic and chemopreventive properties. However, the use of retinoids in the cancer clinic is often hindered by side effects and resistance to treatment. In fact, all-trans retinoic acid (ATRA) is a naturally occurring retinoid that failed phase-II clinical trials in patients with metastatic breast cancer. To overcome retinoids limitations, synthetic retinoids were developed namely, the atypical adamantly retinoid ST1926 which has reduced toxicity and increased specificity. In the present study, we investigated the anti-tumor activities of ATRA, ST1926, and their combinations on the proliferation and cell death of human breast normal and cancer cell lines in 2D and 3D culture models, and the molecular mechanisms involved. We have shown that in 2D culture models, the breast cancer cells MCF-7 and MDA-MB-231 cells are resistant to ATRA while being sensitive to ST1926 at sub-micromolar (µM) concentrations. ST1926-induced growth inhibition persisted after drug removal in breast cancer cells, and spared the ‘normal-like’ MCF-10A and HMT-3522 S1 breast epithelial cells. ST1926 induced massive apoptosis, S-phase arrest, and increased the protein expression levels of the tumor suppressors p53 and p21. ST1926 also caused early DNA damage, downregulated the Wnt-β-catenin pathway, and modulated the expression levels of the different retinoid receptors. ATRA and ST1926 synergized at low sub-µM concentrations to potently inhibit the growth of breast cancer cells, independently of