Abstract B14: Sprouty4 regulates the transition to invasive breast ductal carcinoma through ERK/MAPK signaling

Abstract

Abstract Breast cancer is one of the most common oncologic developments in U.S. women, with approximately 25% of these cases being in situ disease (DCIS). For many years DCIS lesions have been treated using surgery and radiotherapy with the goal of decreasing the amount of late-stage disease. Unfortunately, a number of reports have since shown that early intervention is not sufficient and have highlighted the likelihood of overtreatment. This is especially true for triple-negative breast cancers, which are more strongly associated with distant recurrence, metastasis, and death compared to other types of invasive breast ductal carcinoma (IDC). These factors have generated a substantial clinical need for reliable biomarkers or molecular determinants to assess disease progression. Sprouty proteins are recognized as important regulators of ERK/MAPK signaling, and have been studied in various cancers. We hypothesize that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling, and its loss or reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry we found that Sprouty4 expression was reduced in IDC patient tissue samples compared to normal or DCIS tissues, and that ERK/MAPK activity had an inverse relationship to Sprouty4 expression. These results correspond with immunoblot data from our 3D culture model of breast cancer progression in which Sprouty4 expression was higher during DCIS than in the IDC stage. Efficient overexpression of Sprouty4 reduced both ERK/MAPK activity as well as the aggressive phenotype of MCF10.CA1d IDC cells. Immunofluorescence experiments revealed data consistent with the relocation of E-cadherin back to the cell surface and the restoration of adherens junctions. To determine whether these effects were due to changes in ERK/MAPK signaling, IDC cells were treated with MEK162, an allosteric MEK inhibitor. Nanomolar concentrations of drug produced the restoration of an epithelial-like phenotype similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 may act to control ERK/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions. Citation Format: Ethan J. Brock, Ryan Jackson, Julie L. Boerner, Quanwen Li, Bonnie F. Sloane, Raymond R. Mattingly. Sprouty4 regulates the transition to invasive breast ductal carcinoma through ERK/MAPK signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B14.