Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer
Triple-negative breast cancer (TNBC) has a poor outcome compared to other breast cancer subtypes, and new therapies that target the molecular alterations driving tumor progression are needed. Annexin A1 is an abundant multi-functional Ca<sup>2+</sup> binding and membrane-associated prote...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/5/1154 |
| _version_ | 1797412360733851648 |
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| author | Cameron N. Johnstone Yan Tu Shenna Langenbach David Baloyan Andrew D. Pattison Peter Lock Kara L. Britt Brian D. Lehmann Traude H. Beilharz Matthias Ernst Robin L. Anderson Alastair G. Stewart |
| author_facet | Cameron N. Johnstone Yan Tu Shenna Langenbach David Baloyan Andrew D. Pattison Peter Lock Kara L. Britt Brian D. Lehmann Traude H. Beilharz Matthias Ernst Robin L. Anderson Alastair G. Stewart |
| author_sort | Cameron N. Johnstone |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) has a poor outcome compared to other breast cancer subtypes, and new therapies that target the molecular alterations driving tumor progression are needed. Annexin A1 is an abundant multi-functional Ca<sup>2+</sup> binding and membrane-associated protein. Reported roles of Annexin A1 in breast cancer progression and metastasis are contradictory. Here, we sought to clarify the functions of Annexin A1 in the development and progression of TNBC. The association of Annexin A1 expression with patient prognosis in subtypes of TNBC was examined. Annexin A1 was stably knocked down in a panel of human and murine TNBC cell lines with high endogenous Annexin A1 expression that were then evaluated for orthotopic growth and spontaneous metastasis in vivo and for alterations in cell morphology in vitro. The impact of Annexin A1 knockdown on the expression of genes involved in mammary epithelial cell differentia tion and epithelial to mesenchymal transition was also determined. Annexin A1 mRNA levels correlated with poor patient prognosis in basal-like breast tumors and also in the basal-like 2 subset of TNBCs. Unexpectedly, loss of Annexin A1 expression had no effect on either primary tumor growth or spontaneous metastasis of MDA-MB-231_HM xenografts, but abrogated the growth rate of SUM149 orthotopic tumors. In an MMTV-PyMT driven allograft model of breast cancer, Annexin A1 depletion markedly delayed tumor formation in both immuno-competent and immuno-deficient mice and induced epithelial to mesenchymal transition and upregulation of basal markers. Finally, loss of Annexin A1 resulted in the loss of a discrete CD24<sup>+</sup>/Sca1<sup>−</sup> population containing putative tumor initiating cells. Collectively, our data demonstrate a novel cell-autonomous role for Annexin A1 in the promotion of tumor-forming capacity in a model of human breast cancer and suggest that some basal-like TNBCs may require high endogenous tumor cell Annexin A1 expression for continued growth. |
| first_indexed | 2024-03-09T05:01:01Z |
| format | Article |
| id | doaj.art-5a31f19aaee44aaf82a9a0ae3da9b855 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T05:01:01Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5a31f19aaee44aaf82a9a0ae3da9b8552023-12-03T12:59:50ZengMDPI AGCancers2072-66942021-03-01135115410.3390/cancers13051154Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast CancerCameron N. Johnstone0Yan Tu1Shenna Langenbach2David Baloyan3Andrew D. Pattison4Peter Lock5Kara L. Britt6Brian D. Lehmann7Traude H. Beilharz8Matthias Ernst9Robin L. Anderson10Alastair G. Stewart11Department of Pharmacology and Therapeutics, University of Melbourne, Parkville 3010, AustraliaDepartment of Pharmacology and Therapeutics, University of Melbourne, Parkville 3010, AustraliaDepartment of Pharmacology and Therapeutics, University of Melbourne, Parkville 3010, AustraliaOlivia Newton-John Cancer Research Institute, Heidelberg 3084, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, AustraliaLa Trobe Bioimaging Platform, La Trobe University, Bundoora 3086, AustraliaPeter MacCallum Cancer Centre, Cancer Research Division, Melbourne 3000, AustraliaVanderbilt-Ingram Cancer Centre, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, AustraliaOlivia Newton-John Cancer Research Institute, Heidelberg 3084, AustraliaSir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3000, AustraliaDepartment of Pharmacology and Therapeutics, University of Melbourne, Parkville 3010, AustraliaTriple-negative breast cancer (TNBC) has a poor outcome compared to other breast cancer subtypes, and new therapies that target the molecular alterations driving tumor progression are needed. Annexin A1 is an abundant multi-functional Ca<sup>2+</sup> binding and membrane-associated protein. Reported roles of Annexin A1 in breast cancer progression and metastasis are contradictory. Here, we sought to clarify the functions of Annexin A1 in the development and progression of TNBC. The association of Annexin A1 expression with patient prognosis in subtypes of TNBC was examined. Annexin A1 was stably knocked down in a panel of human and murine TNBC cell lines with high endogenous Annexin A1 expression that were then evaluated for orthotopic growth and spontaneous metastasis in vivo and for alterations in cell morphology in vitro. The impact of Annexin A1 knockdown on the expression of genes involved in mammary epithelial cell differentia tion and epithelial to mesenchymal transition was also determined. Annexin A1 mRNA levels correlated with poor patient prognosis in basal-like breast tumors and also in the basal-like 2 subset of TNBCs. Unexpectedly, loss of Annexin A1 expression had no effect on either primary tumor growth or spontaneous metastasis of MDA-MB-231_HM xenografts, but abrogated the growth rate of SUM149 orthotopic tumors. In an MMTV-PyMT driven allograft model of breast cancer, Annexin A1 depletion markedly delayed tumor formation in both immuno-competent and immuno-deficient mice and induced epithelial to mesenchymal transition and upregulation of basal markers. Finally, loss of Annexin A1 resulted in the loss of a discrete CD24<sup>+</sup>/Sca1<sup>−</sup> population containing putative tumor initiating cells. Collectively, our data demonstrate a novel cell-autonomous role for Annexin A1 in the promotion of tumor-forming capacity in a model of human breast cancer and suggest that some basal-like TNBCs may require high endogenous tumor cell Annexin A1 expression for continued growth.https://www.mdpi.com/2072-6694/13/5/1154Annexin A1breast cancermouse modelallograftxenograft |
| spellingShingle | Cameron N. Johnstone Yan Tu Shenna Langenbach David Baloyan Andrew D. Pattison Peter Lock Kara L. Britt Brian D. Lehmann Traude H. Beilharz Matthias Ernst Robin L. Anderson Alastair G. Stewart Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer Cancers Annexin A1 breast cancer mouse model allograft xenograft |
| title | Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer |
| title_full | Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer |
| title_fullStr | Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer |
| title_full_unstemmed | Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer |
| title_short | Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer |
| title_sort | annexin a1 is required for efficient tumor initiation and cancer stem cell maintenance in a model of human breast cancer |
| topic | Annexin A1 breast cancer mouse model allograft xenograft |
| url | https://www.mdpi.com/2072-6694/13/5/1154 |
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