FABP7 and HMGCS2 are novel protein markers for apocrine differentiation categorizing apocrine carcinoma of the breast

PLoS One. 2014 Nov 12;9(11):e112024. doi: 10.1371/journal.pone.0112024. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies / chemistry
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / metabolism*
  • Carcinoma / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Differentiation
  • Cell Line, Tumor
  • Disease Progression
  • Fatty Acid-Binding Protein 7
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hydroxymethylglutaryl-CoA Synthase / metabolism*
  • Immunohistochemistry
  • Middle Aged
  • Reproducibility of Results
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Antibodies
  • Biomarkers, Tumor
  • Carrier Proteins
  • FABP7 protein, human
  • Fatty Acid-Binding Protein 7
  • HMGCS2 protein, human
  • Tumor Suppressor Proteins
  • Hydroxymethylglutaryl-CoA Synthase

Grant support

This work was supported by grants from the Danish Cancer Society, the John and Birthe Meyer Foundation, the Kai Lange and Gundhild Kai Lange Fond, and the Lisa and Gudmund JÃ ¸rgensens Fond. The ear-marked support of the Marketing Department at the Danish Cancer Society through their fundraising activities on behalf of DCTB is greatly appreciated. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.