Intracrinology of breast microenvironment: hormonal status in nipple aspirate fluid and its relationship to breast cancer

Mannello, Ferdinando; Medda, Virginia; Smaniotto, Alessandra; Tonti, Gaetana A.

doi:10.1586/eem.09.28

Cited by 9 publications

(17 citation statements)

References 69 publications

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“…NAF contains secreted proteins and cells shed from ductal and lobular epithelium (Mannello et al , ), and several biomarkers (Petrakis, , ; Mannello et al , , ) and proteinases (Mannello and Sebastiani, ; Qin et al , ) of potential use as epidemiological and clinical research tools have been identified (Dua et al , ). In addition, the intracrinology of NAF has provided a further panel of cancer biomarkers reflecting the hormonal status in the breast microenvironment (Mannello et al , ). On the basis of its composition, NAF has been classified into two types: (1) NoCancer NAF taken from healthy control women or patients diagnosed with benign breast diseases; and (2) Cancer NAF taken from women affected by breast carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer‐affected patients

Mannello

Tonti

Medda

et al. 2011

J of Applied Toxicology

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Aluminium is not a physiological component of the breast but has been measured recently in human breast tissues and breast cyst fluids at levels above those found in blood serum or milk. Since the presence of aluminium can lead to iron dyshomeostasis, levels of aluminium and iron-binding proteins (ferritin, transferrin) were measured in nipple aspirate fluid (NAF), a fluid present in the breast duct tree and mirroring the breast microenvironment. NAFs were collected noninvasively from healthy women (NoCancer; n = 16) and breast cancer-affected women (Cancer; n = 19), and compared with levels in serum (n = 15) and milk (n = 45) from healthy subjects. The mean level of aluminium, measured by ICP-mass spectrometry, was significantly higher in Cancer NAF (268.4 ± 28.1 μg l(-1) ; n = 19) than in NoCancer NAF (131.3 ± 9.6 μg l(-1) ; n = 16; P < 0.0001). The mean level of ferritin, measured through immunoassay, was also found to be higher in Cancer NAF (280.0 ± 32.3 μg l(-1) ) than in NoCancer NAF (55.5 ± 7.2 μg l(-1) ), and furthermore, a positive correlation was found between levels of aluminium and ferritin in the Cancer NAF (correlation coefficient R = 0.94, P < 0.001). These results may suggest a role for raised levels of aluminium and modulation of proteins that regulate iron homeostasis as biomarkers for identification of women at higher risk of developing breast cancer. The reasons for the high levels of aluminium in NAF remain unknown but possibilities include either exposure to aluminium-based antiperspirant salts in the adjacent underarm area and/or preferential accumulation of aluminium by breast tissues.

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Section: Introductionmentioning

confidence: 99%

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer‐affected patients

Mannello

Tonti

Medda

et al. 2011

J of Applied Toxicology

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“…In fact, the secretome of NAF samples (noninvasively collected fluids from all breast cancer patients [27,28]) allow analysis of all the metabolites secreted by epithelial and stromal cells lining the breast ductal/lobular tree, representing the mirror breast microenvironment. The NAF secretome would represent a great opportunity for early diagnosis of breast cancer, limiting the decreased tumour-specificity of surrogate breast cancer biomarkers circulating in the blood.…”

Section: Reviewmentioning

confidence: 99%

“…The intraductal noninvasive approach of NAF secretome analyses may provide a panel of candidate biomarkers strengthening the armoury against BC [27,28]. All studies on the breast microenvironment have shown that the proliferation, survival, polarity, differentiation state, and invasive capacity of breast cancer cells can be modulated by myoepithelial and various stromal cells, mainly through signal molecules (such as growth factors, cytokines, glycosaminoglycans, proteases, hormones, etc.)…”

Section: Reviewmentioning

confidence: 99%

“…All these studies have highlighted NAF as the optimal mirror of the breast microenvironment, in which ductal/lobular/stromal cell products, protein and hormonal components are secreted and/or accumulated during physio-pathologic conditions [27,28]. Also, among the wide number of bio-compounds present in NAF, proteinase analyses have gained increasing attention due to their role in the degradative balance into breast microenvironment at the tumor-host interface [62,63].…”

Section: Reviewmentioning

confidence: 99%

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

Mannello

Ligi

2013

BMC Cancer

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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.

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“…1 Nipple aspirate fluid (NAF) is a biological fluid produced by the breast ductal epithelium that can be collected from the breast nipple by gentle aspiration in 36–98% of healthy, nonlactating women. 2–4 The breast is first massaged before NAF is aspirated from the nipple using a hand-held suction cup. Microcapillary tubes are used to collect the fluid, which is then diluted with phosphate buffered saline (PBS) to ease handling.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic Characterization of Nipple Aspirate Fluid by¹H NMR Spectroscopy and GC-MS

et al. 2014

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Nipple aspirate fluid (NAF) is a noninvasively obtained biofluid from the duct openings of the breast. NAF components are constantly secreted, metabolized, and reabsorbed by the epithelial lining of the lactiferous ducts of the breast. NAF has been studied as a potential breast tissue surrogate for the discovery of novel breast cancer risk, early detection, and treatment response biomarkers. We report the first unsupervised metabolite characterization of nipple aspirate fluid using NMR and GC-MS using convenience samples previously collected from four premenopausal and four postmenopausal women. A total of 38 metabolites were identified using the two analytical techniques, including amino acids, organic acids, fatty acids, and carbohydrates. Analytical reproducibility of metabolites in NAF by GC-MS was high across different extraction and analysis days. Overall, 31 metabolites had a coefficient of variation below 20%. By GC-MS, there were eight metabolites unique to NAF, 19 unique to plasma, and 24 shared metabolites. Correlative analysis of shared metabolites between matched NAF and plasma samples from pre- and postmenopausal women shows almost no correlations, with the exception being lactic acid, which was significantly negatively correlated (R2 = 0.57; P = 0.03). These results suggest that NAF is metabolically distinct from plasma and that the application of metabolomic strategies may be useful for future studies investigating breast cancer risk and intervention response biomarkers.

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Intracrinology of breast microenvironment: hormonal status in nipple aspirate fluid and its relationship to breast cancer

Cited by 9 publications

References 69 publications

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer‐affected patients

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer‐affected patients

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

Metabolomic Characterization of Nipple Aspirate Fluid by¹H NMR Spectroscopy and GC-MS

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Intracrinology of breast microenvironment: hormonal status in nipple aspirate fluid and its relationship to breast cancer

Cited by 9 publications

References 69 publications

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer‐affected patients

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer‐affected patients

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

Metabolomic Characterization of Nipple Aspirate Fluid by1H NMR Spectroscopy and GC-MS

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Metabolomic Characterization of Nipple Aspirate Fluid by¹H NMR Spectroscopy and GC-MS