Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways
Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor prog...
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| Veröffentlicht in: | Breast cancer research : BCR 2013-01, Vol.15 (5), p.R102-R102, Article R102 |
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| creator | Strong, Amy L Strong, Thomas A Rhodes, Lyndsay V Semon, Julie A Zhang, Xiujuan Shi, Zhenzhen Zhang, Shijia Gimble, Jeffrey M Burow, Matthew E Bunnell, Bruce A |
| description | Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression.
Breast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted.
ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI > 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo. These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression.
ASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways. |
| doi_str_mv | 10.1186/bcr3569 |
| format | Article |
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Breast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted.
ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI > 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo. These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression.
ASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways.</description><identifier>ISSN: 1465-542X</identifier><identifier>ISSN: 1465-5411</identifier><identifier>EISSN: 1465-542X</identifier><identifier>DOI: 10.1186/bcr3569</identifier><identifier>PMID: 24176089</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Adipocytes - metabolism ; Adipose tissues ; Analysis ; Animals ; Antibodies ; Aromatase - metabolism ; Biotechnology industry ; Body mass index ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - mortality ; Breast Neoplasms - pathology ; Carcinogenesis ; Care and treatment ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic ; Coculture Techniques ; Cyclin-Dependent Kinase Inhibitor p16 - genetics ; Cyclin-Dependent Kinase Inhibitor p16 - metabolism ; Development and progression ; Diagnosis ; Estrogen Receptor alpha - genetics ; Estrogen Receptor alpha - metabolism ; Estrogens - metabolism ; Estrogens - pharmacology ; Female ; Gene Expression Profiling ; Glutathione S-Transferase pi - genetics ; Glutathione S-Transferase pi - metabolism ; Health aspects ; Humans ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Leptin ; Leptin - genetics ; Leptin - metabolism ; MCF-7 Cells ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Mortality ; Obesity ; Obesity - genetics ; Obesity - metabolism ; Progesterone ; Receptors, Estrogen - metabolism ; Receptors, Progesterone - metabolism ; Risk factors ; Signal Transduction ; Stem Cells - metabolism ; Tumor Burden ; United States ; Viral antibodies ; Women</subject><ispartof>Breast cancer research : BCR, 2013-01, Vol.15 (5), p.R102-R102, Article R102</ispartof><rights>COPYRIGHT 2013 BioMed Central Ltd.</rights><rights>Copyright © 2013 Strong et al.; licensee BioMed Central Ltd. 2013 Strong et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b487t-7d4eed50f2fcc98f5422f8c1df3ef253edc42790e31eeb17fc831185edf0e8003</citedby><cites>FETCH-LOGICAL-b487t-7d4eed50f2fcc98f5422f8c1df3ef253edc42790e31eeb17fc831185edf0e8003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978929/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978929/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27915,27916,53782,53784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24176089$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Strong, Amy L</creatorcontrib><creatorcontrib>Strong, Thomas A</creatorcontrib><creatorcontrib>Rhodes, Lyndsay V</creatorcontrib><creatorcontrib>Semon, Julie A</creatorcontrib><creatorcontrib>Zhang, Xiujuan</creatorcontrib><creatorcontrib>Shi, Zhenzhen</creatorcontrib><creatorcontrib>Zhang, Shijia</creatorcontrib><creatorcontrib>Gimble, Jeffrey M</creatorcontrib><creatorcontrib>Burow, Matthew E</creatorcontrib><creatorcontrib>Bunnell, Bruce A</creatorcontrib><title>Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways</title><title>Breast cancer research : BCR</title><addtitle>Breast Cancer Res</addtitle><description>Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression.
Breast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted.
ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI > 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo. These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression.
ASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways.</description><subject>Adipocytes - metabolism</subject><subject>Adipose tissues</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Aromatase - metabolism</subject><subject>Biotechnology industry</subject><subject>Body mass index</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - mortality</subject><subject>Breast Neoplasms - pathology</subject><subject>Carcinogenesis</subject><subject>Care and treatment</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Transformation, Neoplastic</subject><subject>Coculture Techniques</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</subject><subject>Development and progression</subject><subject>Diagnosis</subject><subject>Estrogen Receptor alpha - genetics</subject><subject>Estrogen Receptor alpha - metabolism</subject><subject>Estrogens - metabolism</subject><subject>Estrogens - pharmacology</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Glutathione S-Transferase pi - genetics</subject><subject>Glutathione S-Transferase pi - metabolism</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Intercellular Signaling Peptides and Proteins - genetics</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Leptin</subject><subject>Leptin - genetics</subject><subject>Leptin - metabolism</subject><subject>MCF-7 Cells</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mortality</subject><subject>Obesity</subject><subject>Obesity - genetics</subject><subject>Obesity - metabolism</subject><subject>Progesterone</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Receptors, Progesterone - metabolism</subject><subject>Risk factors</subject><subject>Signal Transduction</subject><subject>Stem Cells - metabolism</subject><subject>Tumor Burden</subject><subject>United States</subject><subject>Viral antibodies</subject><subject>Women</subject><issn>1465-542X</issn><issn>1465-5411</issn><issn>1465-542X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1Ul1rHCEUldCQTdLQf1CEPuRpEx1nVqcPhRCSthDISwJ9E0evu5YZHdRtmcf88xh2s-xCiw9Xvecczv1A6BMlV5SKxXWnI2sW7RE6pfWimTd19evD3n2GzlL6TQjlohEnaFbVlC-IaE_Ry2MHyeUJq5SCdiqDwarPEFV2wSfsPM4rwJ0LfVhOOFisjBtDApwyDFhD3yc8gHljYvAr5XVRyOshRLcEX7QT7iYMKcdQ3tjACN6Az3hUefVXTekjOraqT3Cxjefo-f7u6fbH_OHx-8_bm4d5Vwue59zUAKYhtrJat8KWsiorNDWWga0aBkbXFW8JMArQUW61YKU1DRhLQBDCztG3je647ophXTxE1csxukHFSQbl5GHGu5Vchj-StVy0VVsEvm4ESjP-I3CY0WGQ28EU8pcNeal6kM7bUCB6cEnLm4bVnAvBREFd_QNVjoHB6eDBuvJ_QLjcEHQMKUWwOzuUyLfN2DPweb_8He59FdgrPMK6Qg</recordid><startdate>20130101</startdate><enddate>20130101</enddate><creator>Strong, Amy L</creator><creator>Strong, Thomas A</creator><creator>Rhodes, Lyndsay V</creator><creator>Semon, Julie A</creator><creator>Zhang, Xiujuan</creator><creator>Shi, Zhenzhen</creator><creator>Zhang, Shijia</creator><creator>Gimble, Jeffrey M</creator><creator>Burow, Matthew E</creator><creator>Bunnell, Bruce A</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20130101</creationdate><title>Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways</title><author>Strong, Amy L ; Strong, Thomas A ; Rhodes, Lyndsay V ; Semon, Julie A ; Zhang, Xiujuan ; Shi, Zhenzhen ; Zhang, Shijia ; Gimble, Jeffrey M ; Burow, Matthew E ; Bunnell, Bruce A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b487t-7d4eed50f2fcc98f5422f8c1df3ef253edc42790e31eeb17fc831185edf0e8003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adipocytes - metabolism</topic><topic>Adipose tissues</topic><topic>Analysis</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Aromatase - metabolism</topic><topic>Biotechnology industry</topic><topic>Body mass index</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - mortality</topic><topic>Breast Neoplasms - pathology</topic><topic>Carcinogenesis</topic><topic>Care and treatment</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cell Transformation, Neoplastic</topic><topic>Coculture Techniques</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</topic><topic>Development and progression</topic><topic>Diagnosis</topic><topic>Estrogen Receptor alpha - genetics</topic><topic>Estrogen Receptor alpha - metabolism</topic><topic>Estrogens - metabolism</topic><topic>Estrogens - pharmacology</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Glutathione S-Transferase pi - genetics</topic><topic>Glutathione S-Transferase pi - metabolism</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Intercellular Signaling Peptides and Proteins - genetics</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Leptin</topic><topic>Leptin - genetics</topic><topic>Leptin - metabolism</topic><topic>MCF-7 Cells</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mortality</topic><topic>Obesity</topic><topic>Obesity - genetics</topic><topic>Obesity - metabolism</topic><topic>Progesterone</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Receptors, Progesterone - metabolism</topic><topic>Risk factors</topic><topic>Signal Transduction</topic><topic>Stem Cells - metabolism</topic><topic>Tumor Burden</topic><topic>United States</topic><topic>Viral antibodies</topic><topic>Women</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Strong, Amy L</creatorcontrib><creatorcontrib>Strong, Thomas A</creatorcontrib><creatorcontrib>Rhodes, Lyndsay V</creatorcontrib><creatorcontrib>Semon, Julie A</creatorcontrib><creatorcontrib>Zhang, Xiujuan</creatorcontrib><creatorcontrib>Shi, Zhenzhen</creatorcontrib><creatorcontrib>Zhang, Shijia</creatorcontrib><creatorcontrib>Gimble, Jeffrey M</creatorcontrib><creatorcontrib>Burow, Matthew E</creatorcontrib><creatorcontrib>Bunnell, Bruce A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Breast cancer research : BCR</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Strong, Amy L</au><au>Strong, Thomas A</au><au>Rhodes, Lyndsay V</au><au>Semon, Julie A</au><au>Zhang, Xiujuan</au><au>Shi, Zhenzhen</au><au>Zhang, Shijia</au><au>Gimble, Jeffrey M</au><au>Burow, Matthew E</au><au>Bunnell, Bruce A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways</atitle><jtitle>Breast cancer research : BCR</jtitle><addtitle>Breast Cancer Res</addtitle><date>2013-01-01</date><risdate>2013</risdate><volume>15</volume><issue>5</issue><spage>R102</spage><epage>R102</epage><pages>R102-R102</pages><artnum>R102</artnum><issn>1465-542X</issn><issn>1465-5411</issn><eissn>1465-542X</eissn><abstract>Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression.
Breast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted.
ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI > 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo. These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression.
ASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>24176089</pmid><doi>10.1186/bcr3569</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adipocytes - metabolism Adipose tissues Analysis Animals Antibodies Aromatase - metabolism Biotechnology industry Body mass index Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - mortality Breast Neoplasms - pathology Carcinogenesis Care and treatment Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic Coculture Techniques Cyclin-Dependent Kinase Inhibitor p16 - genetics Cyclin-Dependent Kinase Inhibitor p16 - metabolism Development and progression Diagnosis Estrogen Receptor alpha - genetics Estrogen Receptor alpha - metabolism Estrogens - metabolism Estrogens - pharmacology Female Gene Expression Profiling Glutathione S-Transferase pi - genetics Glutathione S-Transferase pi - metabolism Health aspects Humans Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Leptin Leptin - genetics Leptin - metabolism MCF-7 Cells Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mortality Obesity Obesity - genetics Obesity - metabolism Progesterone Receptors, Estrogen - metabolism Receptors, Progesterone - metabolism Risk factors Signal Transduction Stem Cells - metabolism Tumor Burden United States Viral antibodies Women |
| title | Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways |
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