Abstract 1517: Retinoic acid-dependent profiles of gene expression in sensitive and resistant breast cancer cell lines

Abstract

Abstract BACKGROUND Breast cancer is a collection of diseases which can be divided in various subgroups according to their profile of gene expression and positivity to estrogen receptor (ER), progesterone receptor (PR) and the tyrosine kinase receptor, HER2. All-trans retinoic acid (ATRA) is a cyto-differentiating agent and it is used in the treatment of acute promyelocytic leukemia with remarkable results. Given its unusual mechanism of action and low level of toxicity, ATRA has raised interest also for the treatment of solid tumors, including breast cancer. Pre-clinical data support the idea that ATRA is a promising agent in the treatment and chemoprevention of certain subgroups of breast cancer, with particular reference to ER+ and HER2+ tumors characterized by co-amplification of the retinoic acid receptor alpha gene. There is also a low proportion of triple-negative breast cancers which show sensitivity to this unusual anti-tumor agent. RESULTS In previous studies, we profiled a large panel of breast cancer cells (>50 lines), representative of the disease heterogeneity, for their sensitivity to the anti-proliferative action of ATRA (Bolis M. et al. Ann Oncol. 2017, 28:611; Centritto F et al.. EMBO Mol Med. 2015, 7:950). To identify gene-networks and gene pathways involved in the anti-proliferative action of ATRA, we performed total RNA-sequencing experiments in a panel of 16 sensitive and resistant cells (8 luminal and 8 triple-negative lines) before and after treatment with the retinoid (1.0 microM) for 48 hours. We identified gene-networks whose expression is selectively modulated by ATRA in retinoid-sensitive luminal and triple-negative cell lines as well as other gene-networks which are commonly regulated in both cell groups. Among the networks stimulated by ATRA, the group of genes involved in interferon-responses is of particular interest, as it indicates that the retinoid exerts a strong and specific immuno-modulatory action in sensitive breast cancer cell lines. A second pathway of relevance is represented by genes involved in the EMT (epithelial-to-mesenchymal transition) process which are down-regulated by ATRA in sensitive luminal cells. We are evaluating the functional significance of specific elements of these gene-networks for the anti-tumor/-metastatic action of ATRA with the use of silencing and over-expression approaches. CONCLUSIONS The results obtained in our cellular models provide insights into the molecular mechanisms underlying the anti-tumor action of ATRA in breast cancer. In addition, the sequencing data led to the identification of ATRA-dependent pathways and gene-networks with significance for the anti-tumor activity of the retinoid. Finally, the approach provides information as to potential new molecular targets for the design of rational therapeutic combinations based on ATRA for the treatment and secondary chemo-prevention of certain types of breast cancer. Citation Format: Marco Bolis. Retinoic acid-dependent profiles of gene expression in sensitive and resistant breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1517.