Identification of a metabolic and canonical biomarker signature in Mexican HR+/HER2-, triple positive and triple-negative breast cancer patients

Abstract

Infiltrating ductal breast cancer (IDC) is the principal tumor associated-malignancy in Mexican women. In IDC, the development of intermittent hypoxia leads to an adaptive response coordinated by the transcriptional factor HIF-lα. In the present pilot, retrospective/cross-sectional study, the HIF-la expression was analyzed in 102 tru-cut biopsies from female patients (51±12 years) without previous clinical treatment and compared to 31 normal breast biopsies. The 102 IDC samples corresponded to 56% of HER2 HR+; 8% of HER2+ HR; 22% of triple positive (HER2+/HR+); and 14% of triple negative (TN, HER27-HR-) subtypes. To assess HIF-lα functionality, proteomic and kinetic analysis of glycolytic as well as mitochondrial enzymes, were determined. Validation of HIF-la as cancer biomarker was assessed by determining the contents of the commonly used biomarkers c-MYC, Ki67, and H- and K-RAS, as well as metastatic and autophagy proteins. Proteomic analysis revealed that HIF-lα, c-MYC, HER2 and COXIV contents were significantly increased in all IDC subtypes vs. normal tissue. The contents and activities of glycolytic proteins were similar between normal and IDC samples, except for HER2- HR+ where a substantial increase of HKII was observed. Significant increase in 20GDH and E-cadherin was detected for TN samples vs. other IDC subtypes and for normal samples. These results clearly indicated that HIF-1α + COXIV + c-MYC (+ HER2 for HER2+ subtype) may be useful to depict a breast cancer metabolic marker pattern for diagnosis, whereas the contents of HIF-1α + c-MYC + 20GDH + E-cadherin may be an alternative useful and reliable signature for TN subtype cancer prognosis.