FABP7 and HMGCS2 are novel protein markers for apocrine differentiation categorizing apocrine carcinoma of the breast.
Apocrine carcinoma of the breast is a distinctive malignancy with unique morphological and molecular features, generally characterized by being negative for estrogen and progesterone receptors, and thus not electable for endocrine therapy. Despite the fact that they are morphologically distinct from other breast lesions, no standard molecular criteria are currently available for their diagnosis. Using gel-based proteomics in combination with mass spectrometry and immunohistochemistry we have identified two novel markers, HMGCS2 and FABP7 that categorize the entire breast apocrine differentiation spectrum from benign metaplasia and cysts to invasive stages. Expression of HMGCS2 and FABP7 is strongly associated with apocrine differentiation; their expression is retained by most invasive apocrine carcinomas (IAC) showing positive immunoreactivity in 100% and 78% of apocrine carcinomas, respectively, as compared to non-apocrine tumors (16.7% and 6.8%). The nuclear localization of FABP7 in tumor cells was shown to be associated with more aggressive stages of apocrine carcinomas. In addition, when added to the panel of apocrine biomarkers previously reported by our group: 15-PGDH, HMGCR and ACSM1, together they provide a signature that may represent a golden molecular standard for defining the apocrine phenotype in the breast. Moreover, we show that combining HMGCS2 to the steroidal profile (HMGCS2+/Androgen Receptor (AR)+/Estrogen Receptor(ER)-/Progesteron Receptor (PR)- identifies IACs with a greater sensitivity (79%) as compared with the steroidal profile (AR+/ER-/PR-) alone (54%). We have also presented a detailed immunohistochemical analysis of breast apocrine lesions with a panel of antibodies against proteins which correspond to 10 genes selected from published transcriptomic signatures that currently characterize molecular apocrine subtype and shown that except for melanophilin that is overexpressed in benign apocrine lesions, these proteins were not specific for morphological apocrine differentiation in breast.
Danish Cancer Society Research Center, Genome Integrity Unit, Copenhagen, Denmark.
Pavel
P
Gromov
Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Jaime A
JA
Espinoza
Department of Pathology, the Centre of Diagnostic Investigations, Copenhagen University Hospital, Copenhagen, Denmark.
Maj-Lis
ML
Talman
Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Naoko
N
Honma
Department of Breast Surgery, Copenhagen University Hospital, Copenhagen, Denmark.
Niels
N
Kroman
Department of Pathology, the Centre of Diagnostic Investigations, Copenhagen University Hospital, Copenhagen, Denmark.
Vera
V
Timmermans Wielenga
Section of Molecular Disease Biology and Sino-Danish Breast Cancer Research Centre, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
José M A
JM
Moreira
Danish Cancer Society Research Center, Genome Integrity Unit, Copenhagen, Denmark.
Irina
I
Gromova
D000328:Adult; D000906:Antibodies / Q000737:chemistry; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018450:Disease Progression; D000071438:Fatty Acid-Binding Protein 7; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism*; D007150:Immunohistochemistry; D008875:Middle Aged; D015203:Reproducibility of Results; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D000906:Antibodies; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C107608:FABP7 protein, human; D000071438:Fatty Acid-Binding Protein 7; C000599408:HMGCS2 protein, human; D025521:Tumor Suppressor Proteins; D006904:Hydroxymethylglutaryl-CoA Synthase