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Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer

1
Department of Pharmacology and Therapeutics, University of Melbourne, Parkville 3010, Australia
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Peter MacCallum Cancer Centre, Cancer Research Division, Melbourne 3000, Australia
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Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3000, Australia
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Olivia Newton-John Cancer Research Institute, Heidelberg 3084, Australia
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School of Cancer Medicine, La Trobe University, Heidelberg 3084, Australia
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Department of Clinical Pathology, University of Melbourne, Melbourne 3000, Australia
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Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, Australia
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La Trobe Bioimaging Platform, La Trobe University, Bundoora 3086, Australia
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Vanderbilt-Ingram Cancer Centre, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
10
ARC Centre for Personalised Therapeutics Technologies, University of Melbourne, Parkville 3010, Australia
*
Authors to whom correspondence should be addressed.
These authors are co-senior authors.
Academic Editor: Paola Marcato
Cancers 2021, 13(5), 1154; https://doi.org/10.3390/cancers13051154
Received: 28 October 2020 / Revised: 22 February 2021 / Accepted: 22 February 2021 / Published: 8 March 2021
(This article belongs to the Section Molecular Cancer Biology)
Triple-negative breast cancer (TNBC) has a poor outcome compared to the other major breast cancer subtypes and new therapies are needed. We sought to clarify the functions of a ubiquitous protein, Annexin A1, in the development and progression of TNBC. We found that Annexin A1 expression correlated with poor patient prognosis in basal-like breast tumors and also in the basal like-2 subset of TNBCs. Stable knockdown of Annexin A1 attenuated the growth of SUM149 xenografts, which model basal-like 2 tumors. In a polyoma middle T antigen-driven allograft model of breast cancer, Annexin A1 depletion markedly delayed tumor formation, induced epithelial to mesenchymal transition and upregulated basal markers. Finally, loss of Annexin A1 resulted in the loss of a discrete CD24+/Sca1 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 certain TNBC tumors.
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 Ca2+ 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+/Sca1 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. View Full-Text
Keywords: Annexin A1; breast cancer; mouse model; allograft; xenograft Annexin A1; breast cancer; mouse model; allograft; xenograft
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MDPI and ACS Style

Johnstone, C.N.; Tu, Y.; Langenbach, S.; Baloyan, D.; Pattison, A.D.; Lock, P.; Britt, K.L.; Lehmann, B.D.; Beilharz, T.H.; Ernst, M.; Anderson, R.L.; Stewart, A.G. Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer. Cancers 2021, 13, 1154. https://doi.org/10.3390/cancers13051154

AMA Style

Johnstone CN, Tu Y, Langenbach S, Baloyan D, Pattison AD, Lock P, Britt KL, Lehmann BD, Beilharz TH, Ernst M, Anderson RL, Stewart AG. Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer. Cancers. 2021; 13(5):1154. https://doi.org/10.3390/cancers13051154

Chicago/Turabian Style

Johnstone, Cameron N., 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, and Alastair G. Stewart 2021. "Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer" Cancers 13, no. 5: 1154. https://doi.org/10.3390/cancers13051154

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