Abstract 3088: Combinations of lapatinib and all-trans retinoic acid control the coordinate expression of microRNA modules and target-mRNAs in ERBB2+/RARA+ breast carcinoma cells: Significance for the antitumor activity.
Authors: Garattini Enrico , Fisher James N. , Paroni Gabriela , Centritto Floriana , Goodall Gregory J. , Tsykin Anna , Fratelli Maddalena , Terao Mineko 
Published: August 2014

In a recent report (Paroni et al, Oncogene, 31:3431-43, 2012), we demonstrated that 25% of all ERBB2+ breast cancers present with a co-amplification of the RARA locus, encoding the nuclear retinoic acid receptor, RARα. ERBB2+/RARA+ breast cancer cell lines, like SKBR3 and AU565, are sensitive to the anti-proliferative and cyto-differentiating effects of all-trans retinoic acid (ATRA), whereas the ERBB2+/RARA− counterparts are refractory. Simultaneous targeting of RARα with ATRA and ERBB2 with lapatinib in SKBR3 and AU565 cells leads to synergistic interactions as to growth inhibition and cyto-differentiation. In addition, combinations of ATRA and lapatinib exert an apoptotic effect, which is not observed with the single components. This suggests that ERBB2+/RARA+ breast cancer patients may benefit from lapatinib+ATRA regimens and represent the rationale of an ongoing clinical trial.

The use of lapatinib and ATRA for the stratified therapy of ERBB2+/RARA+ patients requires knowledge of the molecular mechanisms underlying the cross-talk between the two compounds. We evaluated the effects of lapatinib and/or ATRA on the expression profiles of more than 1,000 microRNAs in SKBR3 cells using an appropriate microarray platform. Both lapatinib and ATRA caused up- and down-regulation of numerous microRNAs. The combination of the two compounds enhanced the action of the single components of the mixture and resulted in the up- and down-regulation of novel target microRNAs as well. We integrated these results with microRNA-target-gene prediction algorithms and whole-genome gene-expression data looking for significant correlations between microRNA and potential/established target mRNA levels. Network analysis led to the identification of two highly interconnected microRNA/target-mRNA modules controlled in opposite directions by lapatinib+ATRA. The first one consists of six microRNAs (miR-1207-5-p, miR-874, miR-134, miR-762, miR-1181 and miR-320c) which are up-regulated by lapatinib+ATRA and control a common set of down-regulated target mRNAs in a coordinate fashion. Most of the mRNAs of the module control cell proliferation in a positive fashion. The second network consists of seven microRNAs (miR-203, miR-125a-5p, miR-193a-5p, miR-210, miR-362-5p, miR-532-5p and miR-342-3p) which are down-regulated by lapatinib+ATRA and control a series of up-regulated target-mRNAs. In this case, the majority of regulated genes is involved in negative regulation of cell proliferation. Coordinated regulation of microRNA sets controlling a common group of genes and functions represents a new concept that deserves further studies. Currently, we are in the process of establishing the functional significance of the identified microRNA modules for the anti-tumor effects of lapatinib and ATRA.

Citation Format: Enrico Garattini, James N. Fisher, Gabriela Paroni, Floriana Centritto, Gregory J. Goodall, Anna Tsykin, Maddalena Fratelli, Mineko Terao. Combinations of lapatinib and all-trans retinoic acid control the coordinate expression of microRNA modules and target-mRNAs in ERBB2+/RARA+ breast carcinoma cells: Significance for the antitumor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3088. doi:10.1158/1538-7445.AM2013-3088