Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant
Background Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ER alpha-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing m...
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| Veröffentlicht in: | Breast cancer research : BCR 2021-05, Vol.23 (1), p.57-57, Article 57 |
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| creator | Jacquemetton, Julien Kassem, Loay Poulard, Coralie Dahmani, Ahmed De Plater, Ludmilla Montaudon, Elodie Sourd, Laura Morisset, Ludivine El Botty, Rania Chateau-Joubert, Sophie Vacher, Sophie Bieche, Ivan Treilleux, Isabelle Tredan, Olivier Marangoni, Elisabetta Le Romancer, Muriel |
| description | Background Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ER alpha-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylER alpha/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. Methods The interaction of ER alpha/Src and ER alpha/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ER alpha+ and 3 ER alpha- PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ER alpha/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ER alpha/Src and ER alpha/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ER alpha+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ER alpha/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ER alpha signaling, since genomic degradation of ER alpha was unaltered in these tumors, whereas the treatment did not diminish the level of ER alpha/PI3K interaction. Interestingly, in 2 ER alpha- models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ER alpha/PI3K interaction. Conclusions Our results demonstrate that ER alpha/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ER alpha+ tumors was associated with a lack of impairment of ER alpha/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ER alpha/PI3K in ER alpha- tumors could constitute a promising therapeutic option. |
| doi_str_mv | 10.1186/s13058-021-01433-8 |
| format | Article |
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Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylER alpha/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. Methods The interaction of ER alpha/Src and ER alpha/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ER alpha+ and 3 ER alpha- PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ER alpha/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ER alpha/Src and ER alpha/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ER alpha+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ER alpha/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ER alpha signaling, since genomic degradation of ER alpha was unaltered in these tumors, whereas the treatment did not diminish the level of ER alpha/PI3K interaction. Interestingly, in 2 ER alpha- models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ER alpha/PI3K interaction. Conclusions Our results demonstrate that ER alpha/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ER alpha+ tumors was associated with a lack of impairment of ER alpha/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ER alpha/PI3K in ER alpha- tumors could constitute a promising therapeutic option.</description><identifier>ISSN: 1465-5411</identifier><identifier>ISSN: 1465-542X</identifier><identifier>EISSN: 1465-542X</identifier><identifier>DOI: 10.1186/s13058-021-01433-8</identifier><identifier>PMID: 34020697</identifier><language>eng</language><publisher>LONDON: Springer Nature</publisher><subject>1-Phosphatidylinositol 3-kinase ; Analysis ; Animals ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biomarker ; Biomarkers, Tumor - metabolism ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cancer therapies ; Care and treatment ; Cell cycle ; Consent ; Cytoplasm ; Drug Resistance, Neoplasm - drug effects ; Endocrine therapy ; Estrogen ; Estrogen receptors ; Estrogen signaling ; Estrogens ; Ethics ; Female ; Fulvestrant ; Fulvestrant - therapeutic use ; Genes ; Genetic aspects ; Genomic analysis ; Genomics ; Humans ; Life Sciences ; Life Sciences & Biomedicine ; Mice ; Middle Aged ; Mutation ; Oncology ; Patients ; PDX ; Phenols ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoinositide-3 Kinase Inhibitors - therapeutic use ; PI3K ; Prognosis ; Proteins ; Proto-Oncogene Proteins pp60(c-src) - metabolism ; PTEN protein ; Receptors, Estrogen - antagonists & inhibitors ; Receptors, Estrogen - metabolism ; Resistance ; Science & Technology ; Signal Transduction - drug effects ; Survival ; Tamoxifen ; Thiazoles - therapeutic use ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Breast cancer research : BCR, 2021-05, Vol.23 (1), p.57-57, Article 57</ispartof><rights>COPYRIGHT 2021 BioMed Central Ltd.</rights><rights>2021. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>The Author(s) 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>12</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000653028100001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c597t-6df9ef1c502f6a9b600b4c395118af31a4f73c0b7edca4c01f6b85e6b64a0c9b3</citedby><cites>FETCH-LOGICAL-c597t-6df9ef1c502f6a9b600b4c395118af31a4f73c0b7edca4c01f6b85e6b64a0c9b3</cites><orcidid>0000-0002-8491-4015 ; 0000-0002-2430-5429 ; 0000-0001-5881-9383 ; 0000-0003-4821-908X ; 0000-0002-0042-6023</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139055/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139055/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2115,27929,27930,39263,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34020697$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03870082$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Jacquemetton, Julien</creatorcontrib><creatorcontrib>Kassem, Loay</creatorcontrib><creatorcontrib>Poulard, Coralie</creatorcontrib><creatorcontrib>Dahmani, Ahmed</creatorcontrib><creatorcontrib>De Plater, Ludmilla</creatorcontrib><creatorcontrib>Montaudon, Elodie</creatorcontrib><creatorcontrib>Sourd, Laura</creatorcontrib><creatorcontrib>Morisset, Ludivine</creatorcontrib><creatorcontrib>El Botty, Rania</creatorcontrib><creatorcontrib>Chateau-Joubert, Sophie</creatorcontrib><creatorcontrib>Vacher, Sophie</creatorcontrib><creatorcontrib>Bieche, Ivan</creatorcontrib><creatorcontrib>Treilleux, Isabelle</creatorcontrib><creatorcontrib>Tredan, Olivier</creatorcontrib><creatorcontrib>Marangoni, Elisabetta</creatorcontrib><creatorcontrib>Le Romancer, Muriel</creatorcontrib><title>Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant</title><title>Breast cancer research : BCR</title><addtitle>BREAST CANCER RES</addtitle><addtitle>Breast Cancer Res</addtitle><description>Background Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ER alpha-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylER alpha/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. Methods The interaction of ER alpha/Src and ER alpha/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ER alpha+ and 3 ER alpha- PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ER alpha/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ER alpha/Src and ER alpha/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ER alpha+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ER alpha/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ER alpha signaling, since genomic degradation of ER alpha was unaltered in these tumors, whereas the treatment did not diminish the level of ER alpha/PI3K interaction. Interestingly, in 2 ER alpha- models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ER alpha/PI3K interaction. Conclusions Our results demonstrate that ER alpha/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ER alpha+ tumors was associated with a lack of impairment of ER alpha/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ER alpha/PI3K in ER alpha- tumors could constitute a promising therapeutic option.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biomarker</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Cell cycle</subject><subject>Consent</subject><subject>Cytoplasm</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Endocrine therapy</subject><subject>Estrogen</subject><subject>Estrogen receptors</subject><subject>Estrogen signaling</subject><subject>Estrogens</subject><subject>Ethics</subject><subject>Female</subject><subject>Fulvestrant</subject><subject>Fulvestrant - therapeutic use</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genomic analysis</subject><subject>Genomics</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Life Sciences & Biomedicine</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Patients</subject><subject>PDX</subject><subject>Phenols</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoinositide-3 Kinase Inhibitors - therapeutic use</subject><subject>PI3K</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins pp60(c-src) - metabolism</subject><subject>PTEN protein</subject><subject>Receptors, Estrogen - antagonists & inhibitors</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Resistance</subject><subject>Science & Technology</subject><subject>Signal Transduction - drug effects</subject><subject>Survival</subject><subject>Tamoxifen</subject><subject>Thiazoles - therapeutic use</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>1465-5411</issn><issn>1465-542X</issn><issn>1465-542X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqNks1u1DAUhSMEoqXwAiyQJTatUMp1nDjOBmkYfloxEl2AVFaW7dgzrjL2EGem6oPxftzMtAOtWKAs_Pedc32dk2UvKZxSKvjbRBlUIoeC5kBLxnLxKDukJa_yqiwuH-_nlB5kz1K6AqC1qMTT7ICVUABv6sPs1ySo7ib5RKIjcxvi0huiQktCDPndOvk5Uj7MR8imoY94Qnpr7GqIPfGBXHy4JMvY2m7ro3ur0kCMCsb2ZMDVYFty7YcFUcTEpfZBDT6GkR0Wllycsy_osvDaj36qW9nOJ6_J8fsfs5o2J9sbuXW3GYurMDzPnjjVJfvidjzKvn_6-G16ls--fj6fTma5qZp6yHnrGuuoqaBwXDWaA-jSsKbC51OOUVW6mhnQtW2NKg1Qx7WoLNe8VGAazY6y851vG9WVXPV-qfobGZWX243Yz6XqB286K3XpAIqioEbYsqkb7UzZGN5AzTjepkKvdzuv1VovsaAN2Ep3z_T-SfALOY8bKShroBoNTnYGiweys8lMjnvARA0gig1F9vi2WB9_rvHV5NInY7tOBRvXSRYVowUrOQdEXz9Ar-K6x_89UiXDXirK_lBzhc364CLe0YymcsI5cnVTF0id_oPCr7WYoxis87h_T1DsBKaPKfXW7RujIMeQy13IJYZcbkMuBYpe_f2Se8ldqhEQO-Da6uiS8RaDuMcAgFcMCkFxBnTqh20Yp3EdBpS--X8p-w0hTRfG</recordid><startdate>20210521</startdate><enddate>20210521</enddate><creator>Jacquemetton, Julien</creator><creator>Kassem, Loay</creator><creator>Poulard, Coralie</creator><creator>Dahmani, Ahmed</creator><creator>De Plater, Ludmilla</creator><creator>Montaudon, Elodie</creator><creator>Sourd, Laura</creator><creator>Morisset, Ludivine</creator><creator>El Botty, Rania</creator><creator>Chateau-Joubert, Sophie</creator><creator>Vacher, Sophie</creator><creator>Bieche, Ivan</creator><creator>Treilleux, Isabelle</creator><creator>Tredan, Olivier</creator><creator>Marangoni, Elisabetta</creator><creator>Le Romancer, Muriel</creator><general>Springer Nature</general><general>BioMed Central Ltd</general><general>BioMed Central</general><general>BMC</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</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>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8491-4015</orcidid><orcidid>https://orcid.org/0000-0002-2430-5429</orcidid><orcidid>https://orcid.org/0000-0001-5881-9383</orcidid><orcidid>https://orcid.org/0000-0003-4821-908X</orcidid><orcidid>https://orcid.org/0000-0002-0042-6023</orcidid></search><sort><creationdate>20210521</creationdate><title>Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant</title><author>Jacquemetton, Julien ; Kassem, Loay ; Poulard, Coralie ; Dahmani, Ahmed ; De Plater, Ludmilla ; Montaudon, Elodie ; Sourd, Laura ; Morisset, Ludivine ; El Botty, Rania ; Chateau-Joubert, Sophie ; Vacher, Sophie ; Bieche, Ivan ; Treilleux, Isabelle ; Tredan, Olivier ; Marangoni, Elisabetta ; Le Romancer, Muriel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c597t-6df9ef1c502f6a9b600b4c395118af31a4f73c0b7edca4c01f6b85e6b64a0c9b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Analysis</topic><topic>Animals</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biomarker</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Care and treatment</topic><topic>Cell cycle</topic><topic>Consent</topic><topic>Cytoplasm</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Endocrine therapy</topic><topic>Estrogen</topic><topic>Estrogen receptors</topic><topic>Estrogen signaling</topic><topic>Estrogens</topic><topic>Ethics</topic><topic>Female</topic><topic>Fulvestrant</topic><topic>Fulvestrant - therapeutic use</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genomic analysis</topic><topic>Genomics</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Life Sciences & Biomedicine</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Oncology</topic><topic>Patients</topic><topic>PDX</topic><topic>Phenols</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoinositide-3 Kinase Inhibitors - therapeutic use</topic><topic>PI3K</topic><topic>Prognosis</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins pp60(c-src) - metabolism</topic><topic>PTEN protein</topic><topic>Receptors, Estrogen - antagonists & inhibitors</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Resistance</topic><topic>Science & Technology</topic><topic>Signal Transduction - drug effects</topic><topic>Survival</topic><topic>Tamoxifen</topic><topic>Thiazoles - therapeutic use</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jacquemetton, Julien</creatorcontrib><creatorcontrib>Kassem, Loay</creatorcontrib><creatorcontrib>Poulard, Coralie</creatorcontrib><creatorcontrib>Dahmani, Ahmed</creatorcontrib><creatorcontrib>De Plater, Ludmilla</creatorcontrib><creatorcontrib>Montaudon, Elodie</creatorcontrib><creatorcontrib>Sourd, Laura</creatorcontrib><creatorcontrib>Morisset, Ludivine</creatorcontrib><creatorcontrib>El Botty, Rania</creatorcontrib><creatorcontrib>Chateau-Joubert, Sophie</creatorcontrib><creatorcontrib>Vacher, Sophie</creatorcontrib><creatorcontrib>Bieche, Ivan</creatorcontrib><creatorcontrib>Treilleux, Isabelle</creatorcontrib><creatorcontrib>Tredan, Olivier</creatorcontrib><creatorcontrib>Marangoni, Elisabetta</creatorcontrib><creatorcontrib>Le Romancer, Muriel</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Breast cancer research : BCR</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jacquemetton, Julien</au><au>Kassem, Loay</au><au>Poulard, Coralie</au><au>Dahmani, Ahmed</au><au>De Plater, Ludmilla</au><au>Montaudon, Elodie</au><au>Sourd, Laura</au><au>Morisset, Ludivine</au><au>El Botty, Rania</au><au>Chateau-Joubert, Sophie</au><au>Vacher, Sophie</au><au>Bieche, Ivan</au><au>Treilleux, Isabelle</au><au>Tredan, Olivier</au><au>Marangoni, Elisabetta</au><au>Le Romancer, Muriel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant</atitle><jtitle>Breast cancer research : BCR</jtitle><stitle>BREAST CANCER RES</stitle><addtitle>Breast Cancer Res</addtitle><date>2021-05-21</date><risdate>2021</risdate><volume>23</volume><issue>1</issue><spage>57</spage><epage>57</epage><pages>57-57</pages><artnum>57</artnum><issn>1465-5411</issn><issn>1465-542X</issn><eissn>1465-542X</eissn><abstract>Background Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ER alpha-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylER alpha/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. Methods The interaction of ER alpha/Src and ER alpha/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ER alpha+ and 3 ER alpha- PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ER alpha/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ER alpha/Src and ER alpha/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ER alpha+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ER alpha/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ER alpha signaling, since genomic degradation of ER alpha was unaltered in these tumors, whereas the treatment did not diminish the level of ER alpha/PI3K interaction. Interestingly, in 2 ER alpha- models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ER alpha/PI3K interaction. Conclusions Our results demonstrate that ER alpha/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ER alpha+ tumors was associated with a lack of impairment of ER alpha/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ER alpha/PI3K in ER alpha- tumors could constitute a promising therapeutic option.</abstract><cop>LONDON</cop><pub>Springer Nature</pub><pmid>34020697</pmid><doi>10.1186/s13058-021-01433-8</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-8491-4015</orcidid><orcidid>https://orcid.org/0000-0002-2430-5429</orcidid><orcidid>https://orcid.org/0000-0001-5881-9383</orcidid><orcidid>https://orcid.org/0000-0003-4821-908X</orcidid><orcidid>https://orcid.org/0000-0002-0042-6023</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-5411 |
| ispartof | Breast cancer research : BCR, 2021-05, Vol.23 (1), p.57-57, Article 57 |
| issn | 1465-5411 1465-542X 1465-542X |
| language | eng |
| recordid | cdi_proquest_journals_2543497513 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; SpringerNature Journals; PubMed Central Open Access; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; EZB-FREE-00999 freely available EZB journals; PubMed Central; Springer Nature OA/Free Journals |
| subjects | 1-Phosphatidylinositol 3-kinase Analysis Animals Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biomarker Biomarkers, Tumor - metabolism Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cancer therapies Care and treatment Cell cycle Consent Cytoplasm Drug Resistance, Neoplasm - drug effects Endocrine therapy Estrogen Estrogen receptors Estrogen signaling Estrogens Ethics Female Fulvestrant Fulvestrant - therapeutic use Genes Genetic aspects Genomic analysis Genomics Humans Life Sciences Life Sciences & Biomedicine Mice Middle Aged Mutation Oncology Patients PDX Phenols Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3 Kinase Inhibitors - therapeutic use PI3K Prognosis Proteins Proto-Oncogene Proteins pp60(c-src) - metabolism PTEN protein Receptors, Estrogen - antagonists & inhibitors Receptors, Estrogen - metabolism Resistance Science & Technology Signal Transduction - drug effects Survival Tamoxifen Thiazoles - therapeutic use Tumors Xenograft Model Antitumor Assays Xenografts |
| title | Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant |
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