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¹ Departments of Pathology,
² Biostatistics and Applied Mathematics,
³ Breast Medical Oncology and
⁴ Surgery, University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
⁵ Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139, USA
⁶ Department of Pathology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208-3479, USA

(Requests for offprints should be addressed to W F Symmans; Email: fsymmans{at}mdanderson.org)

The pathogenesis of breast cancers that do not express estrogen receptors or Her-2/neu receptors (ER–/HER2– phenotype) is incompletely understood. We had observed markedly elevated gene expression of gamma-aminobutyric acid type A (GABA_A) receptor subunit (GABA, GABRP) in some breast cancers with ER–/HER2– phenotype. In this study, transcriptional profiles (TxPs) were obtained from 82 primary invasive breast cancers by oligonucleotide microarrays. Real-time reverse transcription–polymerase chain reaction (RT–PCR) was used to measure GABA gene expression in a separate cohort of 121 invasive breast cancers. GABA gene expression values from TxP and RT–PCR were standardized and compared with clinicopathologic characteristics in the 203 patients. GABA gene expression was increased in 16% of breast cancers (13/82 TxP, 20/ 121 RT–PCR), particularly in breast cancers with ER–/HER2– phenotype (60%), and breast cancers with basal-like genomic profile (60%). The profile of genes coexpressed with GABA in these tumors was consistent with an immature cell type. In multivariate linear regression analysis, the level of GABA gene expression was associated with ER–/HER2– phenotype (P<0.0001), younger age at diagnosis (P=0.0003), and shorter lifetime duration of breastfeeding ( 6 months) in all women (P=0.017) and specifically in parous women (P=0.013). GABA gene expression was also associated with combinations of high grade with ER–/HER2– phenotype (P=0.002), and with Hispanic ethnicity (P=0.036). GABA gene expression is increased in breast cancers of immature (undifferentiated) cell type and is significantly associated with shorter lifetime history of breastfeeding and with high-grade breast cancer in Hispanic women.

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