Resolving breast cancer heterogeneity by searching reliable protein cancer biomarkers in the breast fluid secretome

Abstract

BackgroundOne of the major goals in cancer research is to find and evaluate the early presence of biomarkers in human fluids and tissues. To resolve the complex cell heterogeneity of a tumor mass, it will be useful to characterize the intricate biomolecular composition of tumor microenvironment (the so called cancer secretome), validating secreted proteins as early biomarkers of cancer initiation and progression. This approach is not broadly applicable because of the paucity of well validated and FDA-approved biomarkers and because most of the candidate biomarkers are mainly organ-specific rather than tumor-specific. For these reasons, there is an urgent need to identify and validate a panel of biomarker combinations for early detection of human tumors. This is especially important for breast cancer, the cancer spread most worldwide among women. It is well known that patients with early diagnosed breast cancer live longer, require less extensive treatment and fare better than patients with more aggressive and/or advanced disease.ResultsIn the frame of searching breast cancer biomarkers (especially using nipple aspirate fluid mirroring breast microenvironment), studies have highlighted an optimal combination of well-known biomarkers: uPA + PAI-1 + TF. When individually investigated they did not show perfect accuracy in predicting the presence of breast cancer, whereas the triple combination has been demonstrated to be highly predictive of pre-cancer and/or cancerous conditions, approaching 97-100% accuracy.ConclusionDespite the heterogeneous composition of breast cancer and the difficulties to find specific breast cancer biomolecules, the noninvasive analysis of the nipple aspirate fluid secretome may significantly improve the discovery of promising biomarkers, helping also the differentiation among benign and invasive breast diseases, opening new frontiers in early oncoproteomics.

Nipple aspirate fluid—A liquid biopsy for diagnosing breast health

“…identified the importance of exploring NAF for established biomarkers such as urokinase‐dependent plasminogen activator (uPA) and plasminogen activator inhibitor (PAI‐I), particularly for their role in ECM turnover associated with cancer invasiveness 30. Our analysis of NAF identified approximately 100 proteolytic enzymes, including uPA, MMP9, and matrilysin, which function to modulate stromal composition.…”

“…Of the five laminin isoforms detected, alpha5, beta2, and gamma1 were the most abundant in all NAF samples, indicating the expression of the specific heterotrimer laminin-11 (or laminin-521) normally found in the glomerular basement membrane of the kidney, in the neuromuscular synaptic cleft and in placenta [29]. Overall NAF samples comprised of a high proportion of proteins functioning in the tumor [30]. Our analysis of NAF identified approximately 100 proteolytic enzymes, including uPA, MMP9, and matrilysin, which function to modulate stromal composition.…”

Oncoproteomics: Trials and tribulations

“…Oncoproteomics may be able to reveal novel diagnostic biomarkers that can be used to help monitor prognosis, disease progression and response to treatment. Proteomics has been used for the identification of potential biomarkers or biomarker patterns in various types of cancer to assist in early diagnosis . For example, Sardana et al.…”

“…Oncoproteomics may be able to reveal novel diagnostic biomarkers that can be used to help monitor prognosis, disease progression and response to treatment. Proteomics has been used for the identification of potential biomarkers or biomarker patterns in various types of cancer to assist in early diagnosis [30,41,47,83,103,104]. For example, Sardana et al used strong anion-exchange chromatography followed by tryptic digestion of recovered fractions for qualitative proteomic analysis of CM from the prostate cancer (PCa) cell line PC3 (AR) 6 , leading to the discovery of the novel candidate protein biomarker, Mac-2BP, which was found to be significantly upregulated in PCa patients [105].…”

Single-Cell Analysis: from Innovative Omics to Target Therapy

“…The renewed interest in cell-to-cell variation and its characterization enriched the concept of cellular heterogeneity, so far use, especially referred to cancer phenotypization [1].…”