Sprouty4 is a negative regulator of ERK/MAPK signaling in breast cancer and plays a role in the transition from in situ to invasive disease

Wayne State University, Detroit MI

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Abstract

PROJECT SUMMARY/ABSTRACT Breast ductal carcinoma in situ (DCIS) is a prevalent and non-invasive condition in which abnormal cells proliferate inside the mammary duct. When these cells escape this confined area by invading into the surrounding tissue the lesion is classified as invasive breast ductal carcinoma (IDC), and patient prognosis becomes much less favorable. There are multiple subtypes of IDC, but treatment options are the most limited for those classified as triple-negative breast cancer (TNBC). TNBCs lack the conventional markers for targeted therapy: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression. This leaves chemotherapy as the primary treatment for these patients, though they often respond poorly. TNBC is more strongly associated with distant recurrence, metastasis, and death compared to other types of IDC, underscoring the need for a better understanding of disease progression. While more DCIS lesions are being detected annually, recent reports show that additional information is required for effective disease intervention. A large reason for this is because it remains unclear which DCIS will become invasive and which will remain indolent during the patient?s natural life. As a result, many lesions are addressed via breast conservation surgery and radiotherapy. Under this standard, DCIS that could have been managed with less aggressive therapy is over-treated, resulting in unnecessary patient risk and financial burden. This dilemma has generated a substantial clinical need for reliable biomarkers or molecular determinants to assess disease progression. The proposed study will characterize Sprouty4 in the context of breast cancer progression with a focus on triple-negative disease. We will define the role of Sprouty4 in DCIS and IDC by determining Sprouty4?s clinical expression using patient samples, assessing cellular changes that result from its loss and re-expression by evaluating tumor cell migration and invasion, as well as examining these changes at the mRNA and protein levels through quantitative real-time PCR, immunocytochemistry, and immunoblotting. We will also determine the identity of Sprouty4-binding proteins to understand how this interaction influences the activity of an important proliferative pathway within DCIS and IDC cells by employing mass spectrometry, pull-down, immunoprecipitation, and cellular fractionation techniques, as well as activity assays. Success of the proposed studies would provide a rationale for adding Sprouty4 to the list of prognostic markers screened in breast cancer-related diagnostic exams (such as Oncotype DX). This would afford oncologists an additional marker for characterizing DCIS lesions, and could reduce overtreatment by providing a more defined picture of which lesions need more- or less- aggressive intervention. In addition, these studies may argue for the adjunct use of certain inhibitors in triple-negative disease where treatment options are limited.