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Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion
Article

Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor

1
Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA
2
Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USA
3
Department of Surgery, Albany Medical College, Albany, NY 12208, USA
*
Author to whom correspondence should be addressed.
Academic Editor: David Wong
Cancers 2021, 13(3), 480; https://doi.org/10.3390/cancers13030480
Received: 16 December 2020 / Revised: 13 January 2021 / Accepted: 20 January 2021 / Published: 27 January 2021
Metastatic 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. View Full-Text
Keywords: triple-negative breast cancer; integrin α3β1; tumor cell invasion; metastasis; Brain-2; Brn-2; Oct-7; N-Oct3; POU3F2 triple-negative breast cancer; integrin α3β1; tumor cell invasion; metastasis; Brain-2; Brn-2; Oct-7; N-Oct3; POU3F2
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MDPI and ACS Style

Miskin, R.P.; Warren, J.S.A.; Ndoye, A.; Wu, L.; Lamar, J.M.; DiPersio, C.M. Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor. Cancers 2021, 13, 480. https://doi.org/10.3390/cancers13030480

AMA Style

Miskin RP, Warren JSA, Ndoye A, Wu L, Lamar JM, DiPersio CM. Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor. Cancers. 2021; 13(3):480. https://doi.org/10.3390/cancers13030480

Chicago/Turabian Style

Miskin, Rakshitha P., Janine S.A. Warren, Abibatou Ndoye, Lei Wu, John M. Lamar, and C. M. DiPersio 2021. "Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor" Cancers 13, no. 3: 480. https://doi.org/10.3390/cancers13030480

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