Abstract
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.
Highlights
Apocrine carcinoma of the breast exhibits the same histological growth pattern as invasive ductal carcinoma of no special type, and is currently diagnosed on basis of the presence of characteristic apocrine-type epithelial cell morphology observed in more than 90% of tumor cell mass
The results show that HMGCS2 and FABP7 are recognized by their corresponding antibodies, and, most importantly, crossreactivity was detected for neither HMGCS2 nor FABP7 with any of the thousands of proteins resolved by 2D PAGE, demonstrating a high specificity for these antibodies
The strategy we have employed to generate protein markers to categorize invasive apocrine carcinomas (IACs) and potentially be used as targets for therapy, is based on the assumption that these lesions arise from apocrine cells, which in turn are derived from normal breast epithelial luminal cells that have undergone apocrine metaplasia [1], i.e. transition from breast epithelial cells into an apocrine sweat-gland type of cells [2,19,28]
Summary
Apocrine carcinoma of the breast exhibits the same histological growth pattern as invasive ductal carcinoma of no special type, and is currently diagnosed on basis of the presence of characteristic apocrine-type epithelial cell morphology observed in more than 90% of tumor cell mass. These tumors represent a relatively rare subtype, constituting less than 5% of all breast cancers [1,2]. Dellapasqua and coauthors reported a frequency of apocrine carcinoma of 0.8% after analyzing a cohort of 6971 breast cancer patients [3]. A comprehensive study published recently has revealed a significantly worse disease free survival for pure IACs as compared with invasive ductal carcinoma (IDC) [3]
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