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Annexin A8 Is Up-Regulated During Mouse Mammary Gland Involution and Predicts Poor Survival in Breast Cancer

Authors' Affiliations: ¹ Division of Cancer Sciences and Molecular Pathology, Western Infirmary; ² Faculty of Veterinary Medicine, University of Glasgow; ³ Department of Pathology, Western Infirmary, Glasgow, United Kingdom; ⁴ Frontier Science and Technology Research Foundation, Boston, MA; ⁵ Structural Cell Biology Unit, Institute of Medical Anatomy, The Panum Institute, Copenhagen, Denmark; and ⁶ Institute of Pathology, University Hospital Basel, Basel, Switzerland

Requests for reprints: Barry A. Gusterson, Division of Cancer Sciences and Molecular Pathology, Western Infirmary, University of Glasgow, Glasgow, G11 6NT, United Kingdom. Phone: 141-211-2233; Fax: 141-337-2494; E-mail: bag5f{at}clinmed.gla.ac.uk.

Purpose: Microarray studies have linked Annexin A8 RNA expression to a "basal cell–like" subset of breast cancers, including BRCA1-related cancers, that are characterized by cytokeratin 5 (CK5) and CK17 expression and show poor prognosis. We assessed Annexin A8's contribution to the overall prognosis and its expression in normal, benign, and cancerous tissue and addressed Annexin A8's physiologic role in the mammary gland.

Experimental Design: Using microarrays and reverse transcription-PCR, the Annexin A8 expression was studied during mouse mammary gland development and in isolated mammary structures. Reverse transcription-PCR on cultured human luminal and basal cells, along with immunocytochemistry on normal and benign breast tissues, was used for cellular localization. Annexin A8's prognostic relevance and its coexpression with CK5 were assessed on tissue arrays of 1,631 cases of invasive breast cancer. Coexpression was further evaluated on a small cohort of 14 BRCA1-related breast cancers.

Results: Annexin A8 was up-regulated during mouse mammary gland involution and in pubertal ductal epithelium. Annexin A8 showed preferred expression in cultured basal cells but predominant luminal expression in normal human breast tissue in vivo. Hyperplasias and in situ carcinomas showed a strong staining of basal cells. Annexin A8 expression was significantly associated with grade (P < 0.0001), CK5 (P < 0.0001), and estrogen receptor status (P < 0.0001); 85.7% BRCA1-related breast tumors coexpressed Annexin A8 and CK5.

Conclusion: Annexin A8 is involved in mouse mammary gland involution. In humans, it is a luminally expressed protein with basal expression in cell culture and in hyperplasia/ductal carcinoma in situ. Expression in invasive breast carcinomas has a significant effect on survival (P = 0.03) but is not independent of grade or CK5.

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