In Vitro and In Vivo Effects of Conjugated Linoleic Acid on Mammary Tumorigenesis

Persistent Link:
http://hdl.handle.net/10150/195806
Title:
In Vitro and In Vivo Effects of Conjugated Linoleic Acid on Mammary Tumorigenesis
Author:
Flowers, Margaret
Issue Date:
2008
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Conjugated linoleic acid (CLA) exhibits multiple biological and molecular activities that have made it the subject of considerable nutrition-related research. Numerous studies support broad acting anti-tumor effects including anti-inflammatory, anti-proliferation, and pro-apoptosis in a variety of model systems. CLA’s ability to influence multiple tumor promoting pathways, without toxicity, may prove valuable in the chemoprevention of breast cancer. The overall objective of this dissertation research was to investigate the potential of CLA in the chemoprevention of breast cancer in a subgroup of women at risk of developing estrogen receptor (ER) negative disease. Overexpression of either the ERBB2 oncogene or the epidermal growth factor receptor (EGFR) is a common event in ER negative breast cancer. To respond to this association, the stated research objective was pursued in relevant model systems. The primary hypothesis was that CLA would downregulate the ERBB2 receptor in vitro and inhibit mammary tumorigenesis in vivo. The t10c12 CLA isomer significantly reduced ERBB2 protein expression in the ERBB2 overexpressing cell line SKBr3. This was accompanied by a decrease in NFκB nuclear localization, cyclooxygenase-2 (COX2)-derived prostaglandin (PG) E2 production, increased apoptosis, and inhibition of proliferation. In contrast to the in vitro data, however 1% dietary CLA had pro-tumor effects in the PyV-mT transgenic mouse model, Mammary gland whole mounts indicated a significant loss of adipose in the CLA-treated group compared to controls that was confirmed by the downregulation of adipocyte-specific genes including PPARγ and adiponectin. CLA’s effect on the adipose was supported by decreases in fatty acid synthase at the protein and mRNA level. cDNA microarray revealed significant downregulation of cytoskeletal and adhesion-related genes in the CLA-treated group. These data suggest CLA’s combined effect on the adipose and epithelial architecture may have promoted tumor growth in this model While the large body of evidence supporting an anti-tumor effect of CLA can not be discounted, the studies herein demonstrate the complexity of its action that may not be captured in simple model systems. Reports of adverse effects of mixed isomers or the t10c12 purified isomer lend caution to supplementation that is supported by our in vivo data.
Type:
text; Electronic Dissertation
Keywords:
breast cancer; conjugate linoleic acid; ERBB2; FASN; HER2/neu; PyV-mT
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Nutritional Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Thompson, Patricia A.
Committee Chair:
Thompson, Patricia A.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleIn Vitro and In Vivo Effects of Conjugated Linoleic Acid on Mammary Tumorigenesisen_US
dc.creatorFlowers, Margareten_US
dc.contributor.authorFlowers, Margareten_US
dc.date.issued2008en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractConjugated linoleic acid (CLA) exhibits multiple biological and molecular activities that have made it the subject of considerable nutrition-related research. Numerous studies support broad acting anti-tumor effects including anti-inflammatory, anti-proliferation, and pro-apoptosis in a variety of model systems. CLA’s ability to influence multiple tumor promoting pathways, without toxicity, may prove valuable in the chemoprevention of breast cancer. The overall objective of this dissertation research was to investigate the potential of CLA in the chemoprevention of breast cancer in a subgroup of women at risk of developing estrogen receptor (ER) negative disease. Overexpression of either the ERBB2 oncogene or the epidermal growth factor receptor (EGFR) is a common event in ER negative breast cancer. To respond to this association, the stated research objective was pursued in relevant model systems. The primary hypothesis was that CLA would downregulate the ERBB2 receptor in vitro and inhibit mammary tumorigenesis in vivo. The t10c12 CLA isomer significantly reduced ERBB2 protein expression in the ERBB2 overexpressing cell line SKBr3. This was accompanied by a decrease in NFκB nuclear localization, cyclooxygenase-2 (COX2)-derived prostaglandin (PG) E2 production, increased apoptosis, and inhibition of proliferation. In contrast to the in vitro data, however 1% dietary CLA had pro-tumor effects in the PyV-mT transgenic mouse model, Mammary gland whole mounts indicated a significant loss of adipose in the CLA-treated group compared to controls that was confirmed by the downregulation of adipocyte-specific genes including PPARγ and adiponectin. CLA’s effect on the adipose was supported by decreases in fatty acid synthase at the protein and mRNA level. cDNA microarray revealed significant downregulation of cytoskeletal and adhesion-related genes in the CLA-treated group. These data suggest CLA’s combined effect on the adipose and epithelial architecture may have promoted tumor growth in this model While the large body of evidence supporting an anti-tumor effect of CLA can not be discounted, the studies herein demonstrate the complexity of its action that may not be captured in simple model systems. Reports of adverse effects of mixed isomers or the t10c12 purified isomer lend caution to supplementation that is supported by our in vivo data.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectbreast canceren_US
dc.subjectconjugate linoleic aciden_US
dc.subjectERBB2en_US
dc.subjectFASNen_US
dc.subjectHER2/neuen_US
dc.subjectPyV-mTen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineNutritional Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorThompson, Patricia A.en_US
dc.contributor.chairThompson, Patricia A.en_US
dc.contributor.committeememberThomson, Cynthia A.en_US
dc.contributor.committeememberWinzerling, Joy J.en_US
dc.contributor.committeememberSchroeder, Joyce A.en_US
dc.contributor.committeememberGerner, Eugene W.en_US
dc.identifier.proquest10164en_US
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