FABP7 and HMGCS2 Are Novel Protein Markers for Apocrine Differentiation Categorizing Apocrine Carcinoma of the Breast

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.

Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer

“…Basal concentrations of all EET isomers were elevated in LM6 and LM6-shLacZ as compared with 231 and 231-iR2L. Relative to LM6 or LM6-shLacZ, the EET levels were significantly lower in LM6-CYP2C19 (all EET isomers), LM6-shFABP4 (5,11,(12)(13)(14), and LM6-shFABP5 (5,6-, 11,12and 14,15-EET isomers) cells. We then measured the intracellular EET levels following 24 h culture in media supplemented with 10 nM EETs (containing the four EET isomers, 2.5 nM each) to investigate the effects of CYP2C19/FABP4/FABP5 gene/protein knockdown on exogenous EET uptake.…”

“…FABPs have varied functions in BC progression. FABP3 is a tumor suppressor, whereas FABP4, FABP5, and FABP7 are associated with poor survival [13][14][15][16]. Among the FABP isoforms, FABP4 and FABP5 likely play critical roles in mammary tumor development [17][18][19][20].…”

HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma

“…In human cancer, the expression of HMGCS2 is different. For example, increased HMGCS2 expression was found in estrogen receptor-negative breast cancer and apocrine carcinoma of the breast [24,25]. In poorly differentiated colon cancer, HMGCS2 protein expression was downregulated [26].…”

Tracking cellular and molecular changes in a species-specific manner during experimental tumor progression in vivo

“…Huh6 cells organize themselves into acini-like structures after several days on the CAM could be regarded as a differentiation process. Interestingly, mitochondrial HMGCS2 , which encodes for an enzyme of the ketogenic pathway, increases 27-fold from T1 to T7 and its expression controls differentiation in colon and breast cancer cells [ 45 , 46 ]. HMGCS2 plays a critical role in tumor progression, since overexpression increases ketone body production, thereby favoring growth and motility of cancer cells [ 47 ].…”