Progesterone Receptor Isoform-Specific Promoter Methylation: Association of PRA Promoter Methylation with Worse Outcome in Breast Cancer Patients
ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study c...
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| Veröffentlicht in: | Clinical cancer research 2011-06, Vol.17 (12), p.4177-4186 |
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| creator | PATHIRAJA, Thushangi N SHETTY, Priya B JELINEK, Jaroslav RONG HE HARTMAIER, Ryan MARGOSSIAN, Astrid L HILSENBECK, Susan G ISSA, Jean-Pierre J OESTERREICH, Steffi |
| description | ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.
We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.
Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group.
Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer. |
| doi_str_mv | 10.1158/1078-0432.CCR-10-2950 |
| format | Article |
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We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.
Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group.
Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-10-2950</identifier><identifier>PMID: 21459801</identifier><identifier>CODEN: CCREF4</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adult ; Aged ; Antineoplastic agents ; Antineoplastic Agents, Hormonal - therapeutic use ; Biological and medical sciences ; Bisulfite ; Breast Neoplasms - diagnosis ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - mortality ; Breast Neoplasms - physiopathology ; DNA Methylation ; Female ; Gene Expression Regulation, Neoplastic - genetics ; Gene Order ; Gynecology. Andrology. Obstetrics ; Humans ; Mammary gland diseases ; Medical sciences ; Middle Aged ; Pharmacology. Drug treatments ; Prognosis ; Promoter Regions, Genetic - genetics ; Protein Isoforms - metabolism ; Receptors, Estrogen - genetics ; Receptors, Progesterone - genetics ; Receptors, Progesterone - metabolism ; Survival Analysis ; Tamoxifen - therapeutic use ; Treatment Outcome ; Tumors</subject><ispartof>Clinical cancer research, 2011-06, Vol.17 (12), p.4177-4186</ispartof><rights>2015 INIST-CNRS</rights><rights>2011 AACR.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-bc07875ff3021975301fd33fe971bf7e7f4715dd5bcf96cee2e0e9b1d6b9fbbd3</citedby><cites>FETCH-LOGICAL-c426t-bc07875ff3021975301fd33fe971bf7e7f4715dd5bcf96cee2e0e9b1d6b9fbbd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24258319$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21459801$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PATHIRAJA, Thushangi N</creatorcontrib><creatorcontrib>SHETTY, Priya B</creatorcontrib><creatorcontrib>JELINEK, Jaroslav</creatorcontrib><creatorcontrib>RONG HE</creatorcontrib><creatorcontrib>HARTMAIER, Ryan</creatorcontrib><creatorcontrib>MARGOSSIAN, Astrid L</creatorcontrib><creatorcontrib>HILSENBECK, Susan G</creatorcontrib><creatorcontrib>ISSA, Jean-Pierre J</creatorcontrib><creatorcontrib>OESTERREICH, Steffi</creatorcontrib><title>Progesterone Receptor Isoform-Specific Promoter Methylation: Association of PRA Promoter Methylation with Worse Outcome in Breast Cancer Patients</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.
We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.
Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group.
Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Hormonal - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Bisulfite</subject><subject>Breast Neoplasms - diagnosis</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - mortality</subject><subject>Breast Neoplasms - physiopathology</subject><subject>DNA Methylation</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Gene Order</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Pharmacology. Drug treatments</subject><subject>Prognosis</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Receptors, Estrogen - genetics</subject><subject>Receptors, Progesterone - genetics</subject><subject>Receptors, Progesterone - metabolism</subject><subject>Survival Analysis</subject><subject>Tamoxifen - therapeutic use</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAQgCNERX_gEUC-IHpJ8dhxnHCotES0VCrqagFxtBxn3DVK4sXOgvoYvDEO3bYgIU7--2bGM1-WPQd6AiCq10BlldOCs5OmWeVAc1YL-ig7ACFkzlkpHqf9HbOfHcb4lVIogBZPsn0GhagrCgfZz2Xw1xgnDH5EskKDm8kHchG99WHIP27QOOsMSdjgE0U-4LS-6fXk_PiGLGL0xv0-EG_JcrX4J0h-uGlNvvgQkVxtJ-MHJG4kbwPqOJFGjybxy4TiOMWn2Z7VfcRnu_Uo-3z27lPzPr-8Or9oFpe5KVg55a1JzUlhLacMaik4BdtxbrGW0FqJ0hYSRNeJ1ti6NIgMKdYtdGVb27bt-FF2ept3s20H7EyqHXSvNsENOtwor536-2V0a3XtvyteC8GkTAle7RIE_22bZqgGFw32vR7Rb6OqJCt4WUlI5PF_SSjKijNZUp5QcYua4GMMaO8_BFTN4tUsVc1SVRI_387iU9yLP7u5j7oznYCXO0BHo3sb0tRdfOAKJioONf8Fvji67g</recordid><startdate>20110615</startdate><enddate>20110615</enddate><creator>PATHIRAJA, Thushangi N</creator><creator>SHETTY, Priya B</creator><creator>JELINEK, Jaroslav</creator><creator>RONG HE</creator><creator>HARTMAIER, Ryan</creator><creator>MARGOSSIAN, Astrid L</creator><creator>HILSENBECK, Susan G</creator><creator>ISSA, Jean-Pierre J</creator><creator>OESTERREICH, Steffi</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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>7TM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110615</creationdate><title>Progesterone Receptor Isoform-Specific Promoter Methylation: Association of PRA Promoter Methylation with Worse Outcome in Breast Cancer Patients</title><author>PATHIRAJA, Thushangi N ; SHETTY, Priya B ; JELINEK, Jaroslav ; RONG HE ; HARTMAIER, Ryan ; MARGOSSIAN, Astrid L ; HILSENBECK, Susan G ; ISSA, Jean-Pierre J ; OESTERREICH, Steffi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-bc07875ff3021975301fd33fe971bf7e7f4715dd5bcf96cee2e0e9b1d6b9fbbd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Hormonal - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Bisulfite</topic><topic>Breast Neoplasms - diagnosis</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - mortality</topic><topic>Breast Neoplasms - physiopathology</topic><topic>DNA Methylation</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic - genetics</topic><topic>Gene Order</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Mammary gland diseases</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Pharmacology. Drug treatments</topic><topic>Prognosis</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Protein Isoforms - metabolism</topic><topic>Receptors, Estrogen - genetics</topic><topic>Receptors, Progesterone - genetics</topic><topic>Receptors, Progesterone - metabolism</topic><topic>Survival Analysis</topic><topic>Tamoxifen - therapeutic use</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PATHIRAJA, Thushangi N</creatorcontrib><creatorcontrib>SHETTY, Priya B</creatorcontrib><creatorcontrib>JELINEK, Jaroslav</creatorcontrib><creatorcontrib>RONG HE</creatorcontrib><creatorcontrib>HARTMAIER, Ryan</creatorcontrib><creatorcontrib>MARGOSSIAN, Astrid L</creatorcontrib><creatorcontrib>HILSENBECK, Susan G</creatorcontrib><creatorcontrib>ISSA, Jean-Pierre J</creatorcontrib><creatorcontrib>OESTERREICH, Steffi</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>PATHIRAJA, Thushangi N</au><au>SHETTY, Priya B</au><au>JELINEK, Jaroslav</au><au>RONG HE</au><au>HARTMAIER, Ryan</au><au>MARGOSSIAN, Astrid L</au><au>HILSENBECK, Susan G</au><au>ISSA, Jean-Pierre J</au><au>OESTERREICH, Steffi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Progesterone Receptor Isoform-Specific Promoter Methylation: Association of PRA Promoter Methylation with Worse Outcome in Breast Cancer Patients</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2011-06-15</date><risdate>2011</risdate><volume>17</volume><issue>12</issue><spage>4177</spage><epage>4186</epage><pages>4177-4186</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><coden>CCREF4</coden><abstract>ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.
We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.
Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group.
Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>21459801</pmid><doi>10.1158/1078-0432.CCR-10-2950</doi><tpages>10</tpages></addata></record> |
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| subjects | Adult Aged Antineoplastic agents Antineoplastic Agents, Hormonal - therapeutic use Biological and medical sciences Bisulfite Breast Neoplasms - diagnosis Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - mortality Breast Neoplasms - physiopathology DNA Methylation Female Gene Expression Regulation, Neoplastic - genetics Gene Order Gynecology. Andrology. Obstetrics Humans Mammary gland diseases Medical sciences Middle Aged Pharmacology. Drug treatments Prognosis Promoter Regions, Genetic - genetics Protein Isoforms - metabolism Receptors, Estrogen - genetics Receptors, Progesterone - genetics Receptors, Progesterone - metabolism Survival Analysis Tamoxifen - therapeutic use Treatment Outcome Tumors |
| title | Progesterone Receptor Isoform-Specific Promoter Methylation: Association of PRA Promoter Methylation with Worse Outcome in Breast Cancer Patients |
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