Proteomic Biomarkers for Bisphenol A–Early Exposure and Women’s Thyroid Cancer

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Abstract

Purpose

For the target treatment and prevention of women’s increased thyroid cancer, we focused on risks of environmental exposure to endocrine disrupting chemicals, particularly bisphenol A (BPA), and its high susceptible exposure-timing, particularly early exposure in lives.

Materials and Methods

Female ICR mice were exposed to BPA in utero and in early life (15, 75, and 300 mg/L of drinking water via pregnant mice and lactation). We identified BPA-responsive proteins in mice thyroid by two-dimensional gel electrophoresis, image analyses, and electrospray ionization quadrupole time-of-flight mass spectrometry. We further analyzed expression of the BPA-responsive proteins in women thyroid cancer patients (n=28).

Results

We found the altered 17 proteins in BPA dose-dependent manner among the thyroid tissues of offspring mice and identified nine proteins of them, including Anxa6, Atp5b, Hspa5, and Vcp, etc. In addition, we observed the positive association between blood BPA levels and mRNA expression of the ANXA6 and VCP not in normal but thyroid cancer tissues.

Conclusion

Our study provides ANXA6 and VCP as proteomic biomarkers for BPA–early life exposure and their potential for women’s thyroid cancer.

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Most cited references 24

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The role of Cdk5 in neuroendocrine thyroid cancer.

Karine Pozo, Emely Castro-Rivera, Chunfeng Tan … (2013)

Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression. Copyright © 2013 Elsevier Inc. All rights reserved.

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Annexin A6 contributes to the invasiveness of breast carcinoma cells by influencing the organization and localization of functional focal adhesions.

Josiah Ochieng, Amos M Sakwe, Rainelli Koumangoye … (2011)

The interaction of annexin A6 (AnxA6) with membrane phospholipids and either specific extracellular matrix (ECM) components or F-actin suggests that it may influence cellular processes associated with rapid plasma membrane reorganization such as cell adhesion and motility. Here, we examined the putative roles of AnxA6 in adhesion-related cellular processes that contribute to breast cancer progression. We show that breast cancer cells secrete annexins via the exosomal pathway and that the secreted annexins are predominantly cell surface-associated. Depletion of AnxA6 in the invasive BT-549 breast cancer cells is accompanied by enhanced anchorage-independent cell growth but cell-cell cohesion, cell adhesion/spreading onto collagen type IV or fetuin-A, cell motility and invasiveness were strongly inhibited. To explain the loss in adhesion/motility, we show that vinculin-based focal adhesions in the AnxA6-depleted BT-549 cells are elongated and randomly distributed. These focal contacts are also functionally defective because the activation of focal adhesion kinase and the phosphoinositide-3 kinase/Akt pathway were strongly inhibited while the MAP kinase pathway remained constitutively active. Compared with normal human breast tissues, reduced AnxA6 expression in breast carcinoma tissues correlates with enhanced cell proliferation. Together this suggests that reduced AnxA6 expression contributes to breast cancer progression by promoting the loss of functional cell-cell and/or cell-ECM contacts and anchorage-independent cell proliferation. Copyright © 2010 Elsevier Inc. All rights reserved.

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Maternal Exposure to Bisphenol-A During Pregnancy Increases Pancreatic β-Cell Growth During Early Life in Male Mice Offspring.

Marta García-Arévalo, Paloma Alonso-Magdalena, Joan-Marc Servitja … (2016)

Alterations during development of metabolic key organs such as the endocrine pancreas affect the phenotype later in life. There is evidence that in utero or perinatal exposure to bisphenol-A (BPA) leads to impaired glucose metabolism during adulthood. However, how BPA exposure during pregnancy affects pancreatic β-cell growth and function in offspring during early life has not been explored. We exposed pregnant mice to either vehicle (control) or BPA (10 and 100 μg/kg·d, BPA10 and BPA100) and examined offspring on postnatal days (P) P0, P21, P30, and P120. BPA10 and BPA100 mice presented lower birth weight than control and subsequently gained weight until day 30. At that age, concentration of plasma insulin, C-peptide, and leptin were increased in BPA-exposed animals in the nonfasting state. Insulin secretion and content were diminished in BPA10 and maintained in BPA100 compared with control. A global gene expression analysis indicated that genes related with cell division were increased in islets from BPA-treated animals. This was associated with an increase in pancreatic β-cell mass at P0, P21, and P30 together with increased β-cell proliferation and decreased apoptosis. On the contrary, at P120, BPA-treated animals presented either equal or decreased β-cell mass compared with control and altered fasting glucose levels. These data suggest that in utero exposure to environmentally relevant doses of BPA alters the expression of genes involved in β-cell growth regulation, incrementing β-cell mass/area, and β-cell proliferation during early life. An excess of insulin signaling during early life may contribute to impaired glucose tolerance during adulthood.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Res Treat

Journal ID (iso-abbrev): Cancer Res Treat

Journal ID (publisher-id): CRT

Title: Cancer Research and Treatment : Official Journal of Korean Cancer Association

Publisher: Korean Cancer Association

ISSN (Print): 1598-2998

ISSN (Electronic): 2005-9256

Publication date (Print): January 2018

Publication date (Electronic): 8 March 2017

Volume: 50

Issue: 1

Pages: 111-117

Affiliations

[1 ]Department of Toxicology, Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women’s University, Seoul, Korea

[2 ]Department of Otolaryngology, Hanyang University College of Medicine, Seoul, Korea

[3 ]Department of Anatomy and Pathology, Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women’s University, Seoul, Korea

[4 ]Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

[5 ]Department of Biomedical and Pharmaceutical Sciences, College of Health Professions and Biomedical Sciences, University of Montana, Missoula, MT, USA

Author notes

Correspondence: Mihi Yang, PhD Department of Toxicology, Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Korea Tel: 82-2-2077-7179 Fax: 82-2-710-9871 E-mail: myang@ 123456sm.ac.kr

[*]

Ho-Sun Lee and Yunkyeong Kang contributed equally to this work.

Article

Publisher ID: crt-2017-001

DOI: 10.4143/crt.2017.001

PMC ID: 5784619

PubMed ID: 28279065

SO-VID: e1b53d0e-b627-437c-9d18-6a76357317a8

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 4 January 2017

Date accepted : 2 March 2017

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Proteomic Biomarkers for Bisphenol A–Early Exposure and Women’s Thyroid Cancer

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Abstract

Purpose

Materials and Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 24

The role of Cdk5 in neuroendocrine thyroid cancer.

Annexin A6 contributes to the invasiveness of breast carcinoma cells by influencing the organization and localization of functional focal adhesions.

Maternal Exposure to Bisphenol-A During Pregnancy Increases Pancreatic β-Cell Growth During Early Life in Male Mice Offspring.

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Cited by 12

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