Prolactin Induced Protein (PIP) is a potential biomarker for early stage and malignant breast cancer

Gangadharan, Anju; Nyirenda, Themba; Patel, Kishan; Jaimes-Delgadillo, Nydia; Coletta, Dominique; Tanaka, Takemi; Walland, Ayal C.; Jameel, Zena; Vedantam, Srinivasa; Tang, Sittinon; Mannion, Ciaran; Lee, Grace Y.; Goy, André; Pecora, Andrew L.; Suh, K. Stephen

doi:10.1016/j.breast.2018.03.015

Cited by 13 publications

(9 citation statements)

References 24 publications

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“…PCA readily separated the groups ( Figure 3 C), and a total of 178 proteins was found to be significantly regulated ( Figure 3 B, Table S6 ). Among these, known biomarkers for MB (FSTL5 [ 31 ]), and other tumor types such as neuroendocrine tumors (ENO2 [ 32 ], FMOD [ 33 ], ART3 [ 34 ], COL6A3 [ 35 ]) and PIP [ 36 ], were found to be significantly up-regulated ( Figure 3 B, dark green). A total of 55 regulated proteins were found to be associated with the gene ontology term “leukocyte mediated immunity [2443]” and/or “defense response [6952]”, ( Figure 3 B, brown), most of them characteristic for myeloid cells such as macrophages and strongly indicating an active involvement of immune cells.…”

Section: Resultsmentioning

confidence: 99%

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

Reichl

Niederstaetter

Boegl

et al. 2020

Cancers

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Molecular classification of medulloblastoma (MB) is well-established and reflects the cell origin and biological properties of tumor cells. However, limited data is available regarding the MB tumor microenvironment. Here, we present a mass spectrometry-based multi-omics pilot study of cerebrospinal fluid (CSF) from recurrent MB patients. A group of age-matched patients without a neoplastic disease was used as control cohort. Proteome profiling identified characteristic tumor markers, including FSTL5, ART3, and FMOD, and revealed a strong prevalence of anti-inflammatory and tumor-promoting proteins characteristic for alternatively polarized myeloid cells in MB samples. The up-regulation of ADAMTS1, GAP43 and GPR37 indicated hypoxic conditions in the CSF of MB patients. This notion was independently supported by metabolomics, demonstrating the up-regulation of tryptophan, methionine, serine and lysine, which have all been described to be induced upon hypoxia in CSF. While cyclooxygenase products were hardly detectable, the epoxygenase product and beta-oxidation promoting lipid hormone 12,13-DiHOME was found to be strongly up-regulated. Taken together, the data suggest a vicious cycle driven by autophagy, the formation of 12,13-DiHOME and increased beta-oxidation, thus promoting a metabolic shift supporting the formation of drug resistance and stem cell properties of MB cells. In conclusion, the different omics-techniques clearly synergized and mutually supported a novel model for a specific pathomechanism.

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Section: Resultsmentioning

confidence: 99%

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

Reichl

Niederstaetter

Boegl

et al. 2020

Cancers

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“…In early studies, PIP was shown to be absent in normal breast epithelium, whereas in breast cancers PIP is frequently expressed [ 81 , 82 ]. Others have shown that PIP is frequently present in uninvolved breast tissue [ 84 ]. However, since highly increased levels of PIP have been detected in the peripheral plasma from patients with primary and metastatic breast cancer in comparison to normal subjects, its significance as a potential serum marker in breast cancer is promising [ 51 , 82 , 85 ].…”

Section: Discussionmentioning

confidence: 99%

Secreted indicators of androgen receptor activity in breast cancer pre-clinical models

et al. 2021

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Purpose Accumulating evidence has attracted attention to the androgen receptor (AR) as a biomarker and therapeutic target in breast cancer. We hypothesized that AR activity within the tumor has clinical implications and investigated whether androgen responsive serum factors might serve as a minimally invasive indicator of tumor AR activity. Methods Based on a comprehensive gene expression analysis of an AR-positive, triple negative breast cancer patient-derived xenograft (PDX) model, 163 dihydrotestosterone (DHT)-responsive genes were defined as an androgen responsive gene set. Among them, we focused on genes that were DHT-responsive that encode secreted proteins, namely KLK3, AZGP1 and PIP, that encode the secreted factors prostate specific antigen (PSA), zinc-alpha-2-glycoprotein (ZAG) and prolactin induced protein (PIP), respectively. Using AR-positive breast cancer cell lines representing all breast cancer subtypes, expression of candidate factors was assessed in response to agonist DHT and antagonist enzalutamide. Gene set enrichment analysis (GSEA) was performed on publically available gene expression datasets from breast cancer patients to analyze the relationship between genes encoding the secreted factors and other androgen responsive gene sets in each breast cancer subtype. Results Anti-androgen treatment decreased proliferation in all cell lines tested representing various tumor subtypes. Expression of the secreted factors was regulated by AR activation in the majority of breast cancer cell lines. In GSEA, the candidate genes were positively correlated with an androgen responsive gene set across breast cancer subtypes. Conclusion KLK3, AZGP1 and PIP are AR regulated and reflect tumor AR activity. Further investigations are needed to examine the potential efficacy of these factors as serum biomarkers.

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“…The finding (Vanneste & Naderi, ) that PIP silencing led to a marked reduction in cell adhesion allowed us to interpret PIP silencing could promote migration and invasion in OSCC cells. In addition, Gangadharan et al () similarly observed considerable downregulation of PIP transcription in cancer samples compared with normal breast tissue. We also found PIP expression in OSCC tissue is lower than normal tissue.…”

Section: Discussionmentioning

confidence: 95%

“…PIP has also been shown to belong to a group of salivary proteins, whose profusion is reduced in the presence of oral bleeding (Fleissig et al, ; Haigh et al, ). PIP has also been reported to associate with secretory lesions and is related to atypical and benign precursors (Asirvatham, Falcone, & Kleer, ; Gangadharan et al, ; Gown, Fulton, & Kandalaft, ). In our study, PIP was found to regulate cell proliferation, migration, and invasion of OSCC cells.…”

Section: Discussionmentioning

confidence: 99%

Suppression of OSCC malignancy by oral glands derived‐PIP identified by iTRAQ combined with 2D LC‐MS/MS

Wang

Yuan

Ren

et al. 2019

Journal Cellular Physiology

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Oral squamous cell carcinoma (OSCC) is the most common malignancy in head and neck cancer and a global cause of cancer‐related death. Due to the poor survival rates associated with OSCC, there is a growing need to develop novel technologies and predictive biomarkers to improve disease diagnosis. The identification of new cellular targets in OSCC tumors will benefit such developments. In this study, isobaric tags for relative and absolute quantitation (iTRAQ)‐based proteomics analysis combined with 2‐dimensional liquid chromatography and tandem mass spectrometry (2D LC‐MS/MS) were used to identify differentially expressed proteins (DEPs) between tumor and normal tissues. Of the DEPs detected, the most significantly downregulated protein in OSCC tissue was prolactin‐inducible protein (PIP). Clonogenic and 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) experiments showed that the proliferation capacity of OSCC cells overexpressing PIP decreased due to cell cycle arrest at the G0/G1 checkpoint. Wound‐healing and transwell assay further showed that PIP overexpression also reduced the migration and invasion of OSCC cells. Immunohistochemistry (IHC) was used to analyze the expression in OSCC, indicating that PIP may be secreted by glandular cells and have an inhibitory effect on OSCC cells to produce. In western blot analysis, silencing studies confirmed that PIP mediates these effects through the AKT/mitogen‐activated protein kinase (MAPK) signaling axis in OSCC cells. Taken together, this study reveals PIP as a key mediator of OSCC cell growth, migration, and invasion through its effect on AKT/MAPK signaling.

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Prolactin Induced Protein (PIP) is a potential biomarker for early stage and malignant breast cancer

Abstract: PIP mRNA is significantly downregulated in early stage BC compared to normal breast tissue. Consequently, low PIP mRNA expression in BC tissues could potentially be used as a tissue based biomarker to assist pathologists in confirmation of early stage BC diagnosis.

Cited by 13 publications

References 24 publications

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

Secreted indicators of androgen receptor activity in breast cancer pre-clinical models

Suppression of OSCC malignancy by oral glands derived‐PIP identified by iTRAQ combined with 2D LC‐MS/MS

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