Proteomic Analysis to Identify Breast Cancer Biomarkers in Nipple Aspirate Fluid

Alexander, Hannah; Stegner, Andrew L.; Wagner‐Mann, Colette C.; Bois, Garrett C. Du; Alexander, Stephen; Sauter, Edward R.

doi:10.1158/1078-0432.ccr-04-1002

Cited by 154 publications

(109 citation statements)

References 28 publications

(21 reference statements)

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“…PIP has previously been explored as a NAF‐derived biomarker of breast cancer by proteomics and ELISA methods, and expression found to correlate with pre‐/postmenopausal status and cancer stage 33.…”

Section: Resultsmentioning

confidence: 99%

Nipple aspirate fluid—A liquid biopsy for diagnosing breast health

Shaheed

Tait

Kyriacou

et al. 2017

Proteomics Clinical Apps

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PurposeNipple secretions are protein‐rich and a potential source of breast cancer biomarkers for breast cancer screening. Previous studies of specific proteins have shown limited correlation with clinicopathological features. Our aim, in this pilot study, was to investigate the intra‐ and interpatient protein composition of nipple secretions and the implications for their use as liquid biopsies.Experimental designMatched pairs of nipple discharge/nipple aspirate fluid (NAF, n = 15) were characterized for physicochemical properties and SDS‐PAGE. Four pairs were selected for semiquantitative proteomic profiling and trypsin‐digested peptides analyzed using 2D‐LC Orbitrap Fusion MS. The resulting data were subject to bioinformatics analysis and statistical evaluation for functional significance.ResultsA total of 1990 unique proteins were identified many of which are established cancer‐associated markers. Matched pairs shared the greatest similarity (average Pearson correlation coefficient of 0.94), but significant variations between individuals were observed.Conclusions and clinical relevanceThis was the most complete proteomic study of nipple discharge/nipple aspirate fluid to date providing a valuable source for biomarker discovery. The high level of milk proteins in healthy volunteer samples compared to the cancer patients was associated with galactorrhoea. Using matched pairs increased confidence in patient‐specific protein levels but changes relating to cancer stage require investigation of a larger cohort.

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Section: Resultsmentioning

confidence: 99%

Nipple aspirate fluid—A liquid biopsy for diagnosing breast health

Shaheed

Tait

Kyriacou

et al. 2017

Proteomics Clinical Apps

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“…However, as we omitted samples that were obviously red from our analyses, we considerably reduced the possibility that the hemoglobin identified in our screen was an artifact. In addition, Alexander et al (2004) found the level of hemoglobin b-chain isoforms to be associated with breast cancer in nipple aspirate fluid, which is normally free of blood contamination. As biochemical modifications of the membrane of erythrocytes in women with ovarian cancer may increase susceptibility to hemolysis of red blood cells, a-and b-hemoglobin have been considered as potential markers for ovarian cancer (Kopczynski et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Serum protein signature may improve detection of ductal carcinoma in situ of the breast

et al. 2009

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Ductal carcinoma in situ (DCIS) of the breast is part of a spectrum of preinvasive lesions that originate within normal breast tissue and progress to invasive breast cancer. The detection of DCIS is important for the reduction of mortality from breast cancer, but the diagnosis of preinvasive breast tumors is hampered by the lack of an adequate detection method. To identify the changes in protein expression during the initial stage of tumorigenesis and to identify the presence of new DCIS markers, we analysed serum from 60 patients with breast cancer and 60 normal controls using mass spectrometry. A 23-protein index was generated that correctly distinguishes the DCIS and control groups with sensitivities and specificities in excess of 80% in two independent cohorts. Two candidate peptides were purified and identified as platelet factor 4 (PF-4) and complement C3a desArg anaphylatoxin (C3a desArg ) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In an independent serum set of 165 patients, PF-4 and C3a desArg were significantly upregulated in DCIS compared with non-cancerous controls, as validated using western blot and enzyme-linked immunosorbent assay. We conclude that our serum protein-based test, used in conjunction with image-based screening practices, could improve the sensitivity and specificity of breast cancer detection.

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“…Studies have described in situ and/or infiltrating ductal carcinoma and compared them with normal tissues or non-malignant tumors (64 -71). These approaches have also been applied to biological fluids including serum (72) and nipple aspirate fluids (NAFs) (73). Although 2D electrophoresis has excellent resolution, the requirement for subsequent protein staining and sample handling limits the exhaustivity, sensitivity, and reproducibility of the approach.…”

Section: Mass Spectrometry-based Approachesmentioning

confidence: 99%

Proteomics of Breast Cancer

Bertucci

Birnbaum

Gonçalvès

2006

Molecular & Cellular Proteomics

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Progresses in screening, early diagnosis, prediction of aggressiveness and of therapeutic response or toxicity, and identification of new targets for therapeutic will improve survival of breast cancer. These progresses will likely be accelerated by the new proteomic techniques. In this review, we describe the different techniques currently applied to clinical samples of breast cancer and the most important results obtained with the two most popular proteomic approaches in translational research (tissue microarrays and SELDI-TOF). Molecular & Cellular Proteomics 5:1772-1786, 2006.Worldwide, breast cancer is one of the most frequent and deadly cancers. Although the survival of patients has increased over the last decades in relation with screening programs and postoperative adjuvant systemic therapies (hormone therapy and chemotherapy), many patients die from metastatic relapse. Breast cancer is a complex disease. Accumulation of numerous and often unknown molecular alterations causes cell proliferation, genetic instability, and acquisition of an increasingly invasive and resistant phenotype. The combinatorial origin and the heterogeneity of malignant cells and the variability of the host background create molecularly distinct subgroups of tumors endowed with different phenotypes and clinical outcomes. This heterogeneity is only partially apprehended by the clinicopathological parameters currently used by clinicians, hampering the selection of the most appropriate diagnostic or therapeutic strategy for each case. In addition, current cytotoxic drugs do not differentiate between cancerous and normal cells, causing sometimes disastrous adverse effects. Major efforts aim at characterizing the heterogeneity of the disease by defining more reliable diagnostic/prognostic factors and at developing molecular therapies selectively targeting the tumor cells.For some decades, the study of molecular alterations has successfully elucidated some mechanisms of mammary oncogenesis and identified key genes such as ERBB2, TP53, CCND1, BRCA1, and BRCA2. It has also allowed considerable therapeutic progress by targeting hormonal receptors and ERBB2/HER2 receptor. Today high throughput molecular typing provides an unprecedented opportunity to tackle the combinatory aspect and the complexity of breast cancer. A combination of markers (molecular signature) will probably be more sensitive and specific than a single molecular marker to reflect the actual heterogeneity of disease; more reliable for screening, diagnosis, prognosis, and prediction of therapeutic response; and more useful to find new therapeutic targets. The first large scale techniques applied to the cancer field were DNA microarrays for mRNA expression profiling (1). Several studies have demonstrated the clinical potential of this approach, notably by identifying new biologically relevant and prognostic subclasses of breast cancer unidentifiable by conventional means (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). With the recent development of similar technologies at the DNA...

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Proteomic Analysis to Identify Breast Cancer Biomarkers in Nipple Aspirate Fluid

Cited by 154 publications

References 28 publications

Nipple aspirate fluid—A liquid biopsy for diagnosing breast health

Nipple aspirate fluid—A liquid biopsy for diagnosing breast health

Serum protein signature may improve detection of ductal carcinoma in situ of the breast

Proteomics of Breast Cancer

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