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Annexin a1 is required for efficient tumor initiation and cancer stem cell maintenance in a model of human breast cancer

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posted on 21.04.2021, 06:26 by CN Johnstone, Y Tu, S Langenbach, D Baloyan, AD Pattison, Peter Lock, KL Britt, BD Lehmann, TH Beilharz, Matthias Ernst, Robin Anderson, AG Stewart
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 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. 2+ + −

Funding

This research was supported by National Health and Medical Research Council (Australia) project grants APP1023185 (to A.G.S. and C.N.J.), APP1128250 and APP1042848 (to T.H.B.), and APP1050384 and APP1020280 (to R.L.A.). We acknowledge the support of the Victorian Government Operational Infrastructure Support Program. We acknowledge The Collie Foundation for providing funds to purchase the Aperio slide scanner (Leica Microsystems).

History

Publication Date

01/03/2021

Journal

Cancers

Volume

13

Issue

5

Article Number

ARTN 1154

Pagination

(p. 1-27)

Publisher

MDPI

ISSN

2072-6694

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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