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-1α. In the present pilot, retrospective/cross-sectional study, the HIF-1α 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, HER2-/HR-) subtypes. To assess HIF-1α functionality, proteomic and kinetic analysis of glycolytic as well as mitochondrial enzymes, were determined. Validation of HIF-1α 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-1α, 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 2OGDH 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 + 2OGDH + E-cadherin may be an alternative useful and reliable signature for TN subtype cancer prognosis.

Mitochondrial free fatty acid β-oxidation supports oxidative phosphorylation and proliferation in cancer cells

“…2B) indicated that mitochondrial ␤-oxidation may not be an adequate biomarker for breast tumor identification and prognosis, as it has been proposed for leukemia and myeloma (Samudio et al, 2010;Tirado-Vélez et al, 2012). However, the breast cancer biopsy samples used in the present study were of the HR+ subtype, the dominant type of breast carcinoma in México (Pacheco-Velázquez et al, 2014;Salazar et al, 1996). Thus, it cannot be discarded that mitochondrial ␤-oxidation might still be a suitable biomarker when other breast cancer subtypes are analyzed.…”

“…Thus, it cannot be discarded that mitochondrial ␤-oxidation might still be a suitable biomarker when other breast cancer subtypes are analyzed. For instance, the mitochondrial matrix enzyme complex 2OGDH has been proposed as biomarker for triple negative breast cancer subtype (Pacheco-Velázquez et al, 2014).…”

“…Five infiltrating ductal breast carcinoma samples were collected from female patients at Instituto Nacional de Cancerología, Méx-ico, following the handling protocols approved by the Institutional Ethics Committee and supported by patient's informed consents according to the Declaration of Helsinki (Pacheco-Velázquez et al, 2014). For normal breast tissue, 5 samples were used as a control.…”

“…For normal breast tissue, 5 samples were used as a control. Statistical analysis of human tumor and non-tumor samples was performed by using Student's t-test analyses as described elsewhere (Pacheco-Velázquez et al, 2014).…”

Understanding the cancer cell phenotype beyond the limitations of current omics analyses

“…Presumably such approaches, derived mainly from genomic and metabolomic analyses, could provide strategies for improved cancer diagnosis . In this regard, the contents of some metabolic proteins overexpressed in TN Mexican patients, such as 2‐oxoglutarate dehydrogenase (2OGDH) and the transmembrane protein E‐cadherin associated with migration, have been found to be significantly higher in comparison to the pooled subpopulations of other breast cancer subtypes; this feature together with the analysis of some transcription factors, a protein signature for breast cancer TN subtype (HIF‐1α+c‐MYC + 2OGDH + E‐cadherin) has been proposed . However, the increased contents of these proteins do not necessarily imply an impact in the functioning and regulation of pathways and cellular processes in which they are involved.…”