Abstract 3260: Identification of a novel signaling axis that leads to co-induction of two major actin-regulatory proteins with anti-migratory properties in breast cancer cells

Dysregulation of actin-regulatory proteins is a hallmark feature of tumor malignancy. Along this line, recent studies have established causal relationships between downregulation of expression of actin-binding proteins profilin-1 and -2 (Pfn1, Pfn2 - genes located on chromosomes 17 and 3, respectively) and increasing invasive ability of breast cancer cells. Conversely, genetically elevating expression of these Pfn isoforms suppresses aggressiveness of breast cancer cells. Therefore, identification of a common signaling pathway linking to regulation of these two Pfn isoforms may lead to a novel conceptual strategy to suppress metastatic potential of breast cancer cells in Pfn-dependent manner. We found that hyperactivating RhoA, a member of Rho-family GTPases, causes a marked depletion of cellular Pfn1 and Pfn2 expression, suggesting that a pathway downstream of activated RhoA is one of the major signaling axes for regulating Pfn1 and Pfn2 expression. Through overexpression and knockdown experiments, we further identified MKL1 (megakaryoblastic leukemia-1), a transcriptional co-factor that activates serum-response factor (SRF)-mediated gene transcription downstream of activated Rho, to be a major regulator of expression of Pfn isoforms. However, SRF does not appear to play a role in Rho-dependent Pfn regulation and furthermore, Rho-dependent Pfn regulation occurs post-transcriptionally suggesting that a non-canonical MKL1-linked pathway is involved in co-regulation of Pfn isoforms. Finally, MKL1-dependent induction of Pfn isoforms involves STAT1 and this pathway can be activated pharmacologically resulting in inhibition of breast cancer cell motility. In conclusion, we have identified a novel MKL1-STAT1 signaling axis for co-induction of the two major cellular isoforms of Pfn. This study could open up promising pharmacological points of attack in the context of metastatic breast cancer. Citation Format: Marion Joy, Partha Roy. Identification of a novel signaling axis that leads to co-induction of two major actin-regulatory proteins with anti-migratory properties in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3260. doi:10.1158/1538-7445.AM2015-3260