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Human secretoglobins in normal and neoplastic cells and tissues
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Secretoglobins is a newly described polypeptide family that has gained a lot of interest in human cancer and inflammation research. Although the first secretoglobin polypeptide was discovered more than 30 years ago, their physiological function is still not known. The aim of this thesis was to study the expression of secretoglobins in normal and neoplastic human cells and tissues, and to clarify their possible involvement in human cancer.

We established sensitive and specific quantitative real-time RT-PCR assays for uteroglobin, lipophilins A, B, C, mammaglobin, HIN-1, and UGRP1, and developed specific antibodies for lipophilin B and mammaglobin. By using quantitative real-time RT-PCR, immunohistochemistry, Western blotting, and in situ hybridization, we studied secretoglobin expression in normal and neoplastic cells and tissues.

In normal tissues, real-time RT-PCR analysis showed high expression of mammaglobin in skin. The mammaglobin expression in skin tissue was further confirmed by in situ hybridization and immunohistochemistry, and the expression was shown to be localized to the coiled gland cells of the eccrine sweat glands and the apocrine sweat glands. In addition, we showed by using Western blotting, that mammaglobin was secreted into perspiration from the eccrine sweat glands. In pituitary gland, immunohistochemical analysis showed that lipophilin B was expressed by approximately half of the cells in the anterior pituitary. By using quantitative real-time RT-PCR it was shown that both lipophilins B and C mRNA were expressed in the pituitary gland, therefore we suggested that lipophilins B and C form heterodimers in human pituitary.

In neoplastic tissues, real-time RT-PCR analysis showed dysregulated secretoglobin expression in lung tumors, with down-regulation of uteroglobin and frequent up-regulation of lipophilins A, B, C, and mammaglobin. Immunohistochemical analyses showed down-regulation of mammaglobin in cylindromas versus non-neoplastic eccrine sweat glands and of lipophilin B in pituitary adenomas versus non-neoplastic anterior pituitary. The majority of investigated cell lines showed low, or most often, lack of secretoglobin expression. Nevertheless, it has been shown that mammaglobin is over-expressed in human breast carcinomas. However, ectopic over-expression of mammaglobin and/or lipophilin B had no appreciable effect on cell proliferation rates of Hs578T breast carcinoma cells in vitro. This does not exclude the possibility that secretoglobins could confer some advantage to tumor cells in vivo, but, it indicates that the reported over-expression of mammaglobin is an epiphenomenon not causally involved in breast carcinogenesis.

In summary, our major findings were that mammaglobin was expressed and secreted by the sweat glands of the skin and lipophilin B was expressed by the anterior pituitary gland; and, that expression of mammaglobin and lipophilin B were down-regulated in tumors derived from the same tissues, i.e, in cylindromas and pituitary adenomas, respectively. Furthermore, ectopic over-expression of mammaglobin and lipophilin B in breast carcinoma cells had no appreciable effect on cell proliferation rates in vitro.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2005. , 43 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 956
Keyword [en]
Oncology, secretoglobins, mammaglobin, lipophilin, breast cancer, pituitary, sweat gland
Keyword [sv]
Onkologi
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-490ISBN: 91-7305-853-X (print)OAI: oai:DiVA.org:umu-490DiVA: diva2:143578
Public defence
2005-04-22, Föreläsningssal 244, Lionsalen, 7A, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2005-04-01 Created: 2005-04-01 Last updated: 2012-04-03Bibliographically approved
List of papers
1. Dysregulated secretoglobin expression in human lung cancers
Open this publication in new window or tab >>Dysregulated secretoglobin expression in human lung cancers
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2003 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 41, no 1, 49-56 p.Article in journal (Refereed) Published
Abstract [en]

Lipophilins A, B, C, mammaglobin, and uteroglobin are members of the secretoglobin family of small, secreted, proteins. The functions of these proteins are not well understood but uteroglobin has been implicated in the development of cancers. Uteroglobin is known to be highly expressed in normal lung and down-regulated in lung cancers but expression of the other secretoglobins in normal lung and lung neoplasms have not been investigated. Therefore, we developed quantitative real-time reverse transcription (RT-) PCR assays for the different secretoglobins and evaluated their expression in normal and neoplastic lung tissues. The secretoglobin transcript levels were quantitated by real-time RT-PCR in samples from three normal lungs, 24 lung tumors including six small cell lung carcinomas, seven adenocarcinomas, and five squamous cell carcinomas, and in cell lines from three small cell lung carcinomas and one mesothelioma. Uteroglobin was confirmed to be abundantly expressed in normal lung and the different lung tumors showed down-regulated uteroglobin expression. Of the other secretoglobins, only lipophilin C was detected in normal lung, albeit at low levels. The lung tumors, however, frequently showed neo- or up-regulation of lipophilins A, B, C, and mammaglobin. The results constitute the first quantitative evaluation of secretoglobin expression in normal and neoplastic human lung tissues and demonstrate dysregulation in various human lung cancers. These findings could have important biological and diagnostic implications.

Identifiers
urn:nbn:se:umu:diva-29919 (URN)10.1016/S0169-5002(03)00126-0 (DOI)12826312 (PubMedID)
Available from: 2009-11-27 Created: 2009-11-27 Last updated: 2017-12-12
2. Mammaglobin in normal human sweat glands and human sweat gland tumors
Open this publication in new window or tab >>Mammaglobin in normal human sweat glands and human sweat gland tumors
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2003 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 121, no 2, 428-429 p.Article in journal (Other academic) Published
Identifiers
urn:nbn:se:umu:diva-4458 (URN)10.1046/j.1523-1747.2003.12374.x (DOI)12880439 (PubMedID)
Available from: 2005-04-01 Created: 2005-04-01 Last updated: 2010-08-19Bibliographically approved
3. Secretoglobins in the human pituitary: high expression of lipophilin B and its down-regulation in pituitary adenomas
Open this publication in new window or tab >>Secretoglobins in the human pituitary: high expression of lipophilin B and its down-regulation in pituitary adenomas
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2005 (English)In: Acta Neuropathologica, ISSN 0001-6322, Vol. 109, no 4, 381-386 p.Article in journal (Refereed) Published
Abstract [en]

Secretoglobins are small secreted proteins, the expression of which has mostly been associated with secretory mucosal epithelia. Several secretoglobins have been implicated in the development of various human cancers. Allelic deletions of chromosome 11q13 correlates with the invasiveness of pituitary tumors. Intriguingly, several secretoglobin genes are located on 11q13; however, for most of these genes the expression in the pituitary and pituitary tumors have not been investigated. Antibodies specific for the secretoglobin lipophilin B (SCGB1D2, BU101) were developed and used in an immunohistochemical analysis of a human normal tissue microarray. Prominent lipophilin B immunoreactivity was found in the secretory cells of the anterior pituitary. Eight of nine analyzed pituitary adenomas showed a reduction in lipophilin B immunoreactivity compared to normal pituitary. However, there was no apparent association between lipophilin B immunoreactivity and hormone production or tumor invasiveness. Expression of eight different secretoglobin mRNAs were analyzed in normal pituitary and the pituitary adenoma cell line HP75 by highly specific quantitative real-time reverse transcription-PCR assays. Lipophilins B and C (SCGB2A1, mammaglobin B) were the most prominently expressed secretoglobin mRNAs in the pituitary. No secretoglobin mRNA was detected in the HP75 cells. The present report demonstrates, for the first time, lipophilin B expression in the pituitary and its apparent down-regulation in pituitary adenomas.

Keyword
Secretoglobins, lipophilin, pituitary gland, adenoma
Identifiers
urn:nbn:se:umu:diva-14632 (URN)10.1007/s00401-004-0972-6 (DOI)15668787 (PubMedID)
Available from: 2007-02-27 Created: 2007-02-27 Last updated: 2009-11-27Bibliographically approved
4. Mammaglobin and lipophilin B expression in breast cancer and their lack of effects on breast carcinoma cell proliferation rates
Open this publication in new window or tab >>Mammaglobin and lipophilin B expression in breast cancer and their lack of effects on breast carcinoma cell proliferation rates
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4460 (URN)
Available from: 2005-04-01 Created: 2005-04-01 Last updated: 2010-01-13Bibliographically approved

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