Abstract
Simple SummaryMetastatic triple-negative breast cancer (TNBC) is highly lethal with limited therapy options. Integrin α3β1 is a cell surface receptor that interacts with the extracellular matrix and facilitates communication between tumor cells and their microenvironment. α3β1 is implicated in breast cancer progression and metastasis, so understanding mechanisms by which α3β1 promotes invasion and metastasis will facilitate the development of this integrin as a potential therapeutic target. Here we identify a novel role for α3β1 in promoting the expression of the transcription factor Brain-2 (Brn-2) in triple-negative breast cancer cells. We further report that Brn-2 promotes invasion and metastasis and partially restores invasion to cells in which expression of α3β1 has been suppressed. Bioinformatic analysis of patient datasets revealed a positive correlation between the expression of the genes encoding the integrin α3 subunit and Brn-2. In summary, our work identifies α3β1-mediated induction of Brn-2 as a mechanism that regulates invasive and metastatic properties of breast cancer cells.In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 mRNA and protein and reduced activity of the BRN2 gene promoter. In addition, RNAi-targeting of Brn-2 in MDA-MB-231 cells decreased invasion in vitro and lung colonization in vivo, and exogenous Brn-2 expression partially restored invasion to cells in which α3β1 was suppressed. α3β1 promoted phosphorylation of Akt in MDA-MB-231 cells, and treatment of these cells with a pharmacological Akt inhibitor (MK-2206) reduced both Brn-2 expression and cell invasion, indicating that α3β1-Akt signaling contributes to Brn-2 induction. Analysis of RNAseq data from patients with invasive breast carcinoma revealed that high BRN2 expression correlates with poor survival. Moreover, high BRN2 expression positively correlates with high ITGA3 expression in basal-like breast cancer, which is consistent with our experimental findings that α3β1 induces Brn-2 in TNBC cells. Together, our study demonstrates a pro-invasive/pro-metastatic role for Brn-2 in breast cancer cells and identifies a role for integrin α3β1 in regulating Brn-2 expression, thereby revealing a novel mechanism of integrin-dependent breast cancer cell invasion.
Highlights
Metastatic breast cancer is a highly lethal disease with only a small percentage of patients showing long-term remission in response to available therapies [1]
Our analysis identified the mRNA that encodes Brain-2 (Brn-2/Oct-7/N-Oct3/POU3F2) among the top 15 transcripts that were reduced in α3 knockdown (α3-KD) cells
Suppression of Integrin α3β1 in MDA-MB-231 Cells Decreases the Potential for Studies using human or mouse Triple-negative breast cancer (TNBC) cell lines have shown that expression of integrin α3β1 promotes cell invasion in vitro [13,14,15] and spontaneous metastasis and lung colonization in vivo [17]
Summary
Metastatic breast cancer is a highly lethal disease with only a small percentage of patients showing long-term remission in response to available therapies [1]. A better understanding of the underlying pathology of invasive disease and metastasis will be essential for the identification of novel therapeutic targets and the development of effective treatments for TNBC. The tumor microenvironment (TME) plays a critical role in regulating gene expression programs within tumor cells that drive malignant progression and invasion [4,5]. Tumor cell surface receptors that transmit cues from the TME to regulate gene expression are attractive therapeutic targets. Integrins have emerged as key regulators of both cell-autonomous functions (e.g., proliferation, survival, migration) and cell-mediated modifications of ECM and other elements of the tissue microenvironment that are essential for both normal and pathological tissue remodeling, including tumor growth and progression [7,8,9]. Further investigation is required to understand fully the mechanisms through which specific integrins regulate these processes and the gene expression programs that control them
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