Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor
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 o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/3/480 |
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| author | Rakshitha Pandulal Miskin Janine S. A. Warren Abibatou Ndoye Lei Wu John M. Lamar C. Michael DiPersio |
| author_facet | Rakshitha Pandulal Miskin Janine S. A. Warren Abibatou Ndoye Lei Wu John M. Lamar C. Michael DiPersio |
| author_sort | Rakshitha Pandulal Miskin |
| collection | DOAJ |
| description | 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 <i>BRN2</i> 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 <i>BRN2</i> expression correlates with poor survival. Moreover, high <i>BRN2</i> expression positively correlates with high <i>ITGA3</i> 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. |
| first_indexed | 2024-03-09T03:34:58Z |
| format | Article |
| id | doaj.art-d925648a997f4d47889fe3ceca8870f0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T03:34:58Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d925648a997f4d47889fe3ceca8870f02023-12-03T14:51:03ZengMDPI AGCancers2072-66942021-01-0113348010.3390/cancers13030480Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription FactorRakshitha Pandulal Miskin0Janine S. A. Warren1Abibatou Ndoye2Lei Wu3John M. Lamar4C. Michael DiPersio5Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USADepartment of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USADepartment of Surgery, Albany Medical College, Albany, NY 12208, USADepartment of Surgery, Albany Medical College, Albany, NY 12208, USADepartment of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USADepartment of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USAIn 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 <i>BRN2</i> 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 <i>BRN2</i> expression correlates with poor survival. Moreover, high <i>BRN2</i> expression positively correlates with high <i>ITGA3</i> 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.https://www.mdpi.com/2072-6694/13/3/480triple-negative breast cancerintegrin α3β1tumor cell invasionmetastasisBrain-2Brn-2 |
| spellingShingle | Rakshitha Pandulal Miskin Janine S. A. Warren Abibatou Ndoye Lei Wu John M. Lamar C. Michael DiPersio Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor Cancers triple-negative breast cancer integrin α3β1 tumor cell invasion metastasis Brain-2 Brn-2 |
| title | Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor |
| title_full | Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor |
| title_fullStr | Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor |
| title_full_unstemmed | Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor |
| title_short | Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor |
| title_sort | integrin α3β1 promotes invasive and metastatic properties of breast cancer cells through induction of the brn 2 transcription factor |
| topic | triple-negative breast cancer integrin α3β1 tumor cell invasion metastasis Brain-2 Brn-2 |
| url | https://www.mdpi.com/2072-6694/13/3/480 |
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