Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer
The interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of ER-positive (ER+)/HER2-positive (HER2+) breast cancer and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this cross-talk combining endocrine-th...
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| Veröffentlicht in: | Clinical cancer research 2022-05, Vol.28 (10), p.2167-2179 |
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| creator | Viganò, Lucia Locatelli, Alberta Ulisse, Adele Galbardi, Barbara Dugo, Matteo Tosi, Diego Tacchetti, Carlo Daniele, Tiziana Győrffy, Balázs Sica, Lorenzo Macchini, Marina Zambetti, Milvia Zambelli, Stefania Bianchini, Giampaolo Gianni, Luca |
| description | The interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of ER-positive (ER+)/HER2-positive (HER2+) breast cancer and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this cross-talk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6-inhibition (palbociclib; PFHPert).
Cytotoxic drug effects, interactions, and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-negative (ER-)/HER2+ breast cancer cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ breast cancer treated with neoadjuvant PFHPert in NA-PHER2 trial (NCT02530424).
In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week 2 and surgery were significantly associated to upregulation of senescence-related genes (P = 7.7E-4 and P = 1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (P = 0.019).
Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by cotargeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement. |
| doi_str_mv | 10.1158/1078-0432.CCR-21-3185 |
| format | Article |
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Cytotoxic drug effects, interactions, and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-negative (ER-)/HER2+ breast cancer cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ breast cancer treated with neoadjuvant PFHPert in NA-PHER2 trial (NCT02530424).
In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week 2 and surgery were significantly associated to upregulation of senescence-related genes (P = 7.7E-4 and P = 1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (P = 0.019).
Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by cotargeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.</description><identifier>ISSN: 1078-0432</identifier><identifier>ISSN: 1557-3265</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-21-3185</identifier><identifier>PMID: 35254385</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Cyclin-Dependent Kinase 4 - genetics ; Drug Resistance, Neoplasm - genetics ; Estrogens - metabolism ; Female ; Fulvestrant - pharmacology ; Fulvestrant - therapeutic use ; Humans ; Ki-67 Antigen ; Mechanistic Target of Rapamycin Complex 1 - genetics ; Receptor, ErbB-2 - metabolism ; Receptors, Estrogen - metabolism ; Translational Cancer Mechanisms and Therapy</subject><ispartof>Clinical cancer research, 2022-05, Vol.28 (10), p.2167-2179</ispartof><rights>2022 American Association for Cancer Research.</rights><rights>2022 American Association for Cancer Research 2022 American Association for Cancer Research</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-4a01e4173a17f0c7f7bbce56e1c57b3faccc20c24fd321bd9c0502f050778ee33</citedby><cites>FETCH-LOGICAL-c411t-4a01e4173a17f0c7f7bbce56e1c57b3faccc20c24fd321bd9c0502f050778ee33</cites><orcidid>0000-0002-2372-9625 ; 0000-0002-6790-6267 ; 0000-0003-4538-4354 ; 0000-0002-6465-1078 ; 0000-0003-0251-6433 ; 0000-0003-1424-421X ; 0000-0003-2791-5465</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35254385$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Viganò, Lucia</creatorcontrib><creatorcontrib>Locatelli, Alberta</creatorcontrib><creatorcontrib>Ulisse, Adele</creatorcontrib><creatorcontrib>Galbardi, Barbara</creatorcontrib><creatorcontrib>Dugo, Matteo</creatorcontrib><creatorcontrib>Tosi, Diego</creatorcontrib><creatorcontrib>Tacchetti, Carlo</creatorcontrib><creatorcontrib>Daniele, Tiziana</creatorcontrib><creatorcontrib>Győrffy, Balázs</creatorcontrib><creatorcontrib>Sica, Lorenzo</creatorcontrib><creatorcontrib>Macchini, Marina</creatorcontrib><creatorcontrib>Zambetti, Milvia</creatorcontrib><creatorcontrib>Zambelli, Stefania</creatorcontrib><creatorcontrib>Bianchini, Giampaolo</creatorcontrib><creatorcontrib>Gianni, Luca</creatorcontrib><title>Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>The interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of ER-positive (ER+)/HER2-positive (HER2+) breast cancer and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this cross-talk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6-inhibition (palbociclib; PFHPert).
Cytotoxic drug effects, interactions, and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-negative (ER-)/HER2+ breast cancer cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ breast cancer treated with neoadjuvant PFHPert in NA-PHER2 trial (NCT02530424).
In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week 2 and surgery were significantly associated to upregulation of senescence-related genes (P = 7.7E-4 and P = 1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (P = 0.019).
Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by cotargeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.</description><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cyclin-Dependent Kinase 4 - genetics</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Estrogens - metabolism</subject><subject>Female</subject><subject>Fulvestrant - pharmacology</subject><subject>Fulvestrant - therapeutic use</subject><subject>Humans</subject><subject>Ki-67 Antigen</subject><subject>Mechanistic Target of Rapamycin Complex 1 - genetics</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Translational Cancer Mechanisms and Therapy</subject><issn>1078-0432</issn><issn>1557-3265</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkd1u1DAQhSMEoqXwCCBfcuOux47X2RskGpZSUYTUlmvLcSa7hqy92E6lPg2vitOfFdzYluacM-P5quotsFMA2SyAqYayWvDTtr2iHKiARj6rjkFKRQVfyufl_aQ5ql6l9JMxqIHVL6sjIbmsRSOPqz_fQj-NJrvgSRhI3iJZpxzDBv0CY3fGyRVa3OcQE2ljSIlmM_4i3R1pP32tF0ty4beuc_f-m-g2GyzC6yll4zz25Bo9JoveInH-kHzIpMT4nqznPnQfUom5RXIW0aRMWlNc8XX1YjBjwjeP90n14_P6pv1CL7-fX7QfL6mtATKtDQOsQQkDamBWDarrLMolgpWqE4Ox1nJmeT30gkPXryyTjA_lUKpBFOKk-vCQu5-6HfZl5BzNqPfR7Uy808E4_X_Fu63ehFu9kitZ9lwC3j8GxPB7wpT1zpWfj6PxGKak-VIsGwWCrYpUPkjtvNCIw6ENMD3D1TM4PYPTBa7moGe4xffu3xkPriea4i_PtaMc</recordid><startdate>20220513</startdate><enddate>20220513</enddate><creator>Viganò, Lucia</creator><creator>Locatelli, Alberta</creator><creator>Ulisse, Adele</creator><creator>Galbardi, Barbara</creator><creator>Dugo, Matteo</creator><creator>Tosi, Diego</creator><creator>Tacchetti, Carlo</creator><creator>Daniele, Tiziana</creator><creator>Győrffy, Balázs</creator><creator>Sica, Lorenzo</creator><creator>Macchini, Marina</creator><creator>Zambetti, Milvia</creator><creator>Zambelli, Stefania</creator><creator>Bianchini, Giampaolo</creator><creator>Gianni, Luca</creator><general>American Association for Cancer Research</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2372-9625</orcidid><orcidid>https://orcid.org/0000-0002-6790-6267</orcidid><orcidid>https://orcid.org/0000-0003-4538-4354</orcidid><orcidid>https://orcid.org/0000-0002-6465-1078</orcidid><orcidid>https://orcid.org/0000-0003-0251-6433</orcidid><orcidid>https://orcid.org/0000-0003-1424-421X</orcidid><orcidid>https://orcid.org/0000-0003-2791-5465</orcidid></search><sort><creationdate>20220513</creationdate><title>Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer</title><author>Viganò, Lucia ; Locatelli, Alberta ; Ulisse, Adele ; Galbardi, Barbara ; Dugo, Matteo ; Tosi, Diego ; Tacchetti, Carlo ; Daniele, Tiziana ; Győrffy, Balázs ; Sica, Lorenzo ; Macchini, Marina ; Zambetti, Milvia ; Zambelli, Stefania ; Bianchini, Giampaolo ; Gianni, Luca</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-4a01e4173a17f0c7f7bbce56e1c57b3faccc20c24fd321bd9c0502f050778ee33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cyclin-Dependent Kinase 4 - genetics</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Estrogens - metabolism</topic><topic>Female</topic><topic>Fulvestrant - pharmacology</topic><topic>Fulvestrant - therapeutic use</topic><topic>Humans</topic><topic>Ki-67 Antigen</topic><topic>Mechanistic Target of Rapamycin Complex 1 - genetics</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Translational Cancer Mechanisms and Therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Viganò, Lucia</creatorcontrib><creatorcontrib>Locatelli, Alberta</creatorcontrib><creatorcontrib>Ulisse, Adele</creatorcontrib><creatorcontrib>Galbardi, Barbara</creatorcontrib><creatorcontrib>Dugo, Matteo</creatorcontrib><creatorcontrib>Tosi, Diego</creatorcontrib><creatorcontrib>Tacchetti, Carlo</creatorcontrib><creatorcontrib>Daniele, Tiziana</creatorcontrib><creatorcontrib>Győrffy, Balázs</creatorcontrib><creatorcontrib>Sica, Lorenzo</creatorcontrib><creatorcontrib>Macchini, Marina</creatorcontrib><creatorcontrib>Zambetti, Milvia</creatorcontrib><creatorcontrib>Zambelli, Stefania</creatorcontrib><creatorcontrib>Bianchini, Giampaolo</creatorcontrib><creatorcontrib>Gianni, Luca</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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>Viganò, Lucia</au><au>Locatelli, Alberta</au><au>Ulisse, Adele</au><au>Galbardi, Barbara</au><au>Dugo, Matteo</au><au>Tosi, Diego</au><au>Tacchetti, Carlo</au><au>Daniele, Tiziana</au><au>Győrffy, Balázs</au><au>Sica, Lorenzo</au><au>Macchini, Marina</au><au>Zambetti, Milvia</au><au>Zambelli, Stefania</au><au>Bianchini, Giampaolo</au><au>Gianni, Luca</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2022-05-13</date><risdate>2022</risdate><volume>28</volume><issue>10</issue><spage>2167</spage><epage>2179</epage><pages>2167-2179</pages><issn>1078-0432</issn><issn>1557-3265</issn><eissn>1557-3265</eissn><abstract>The interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of ER-positive (ER+)/HER2-positive (HER2+) breast cancer and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this cross-talk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6-inhibition (palbociclib; PFHPert).
Cytotoxic drug effects, interactions, and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-negative (ER-)/HER2+ breast cancer cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ breast cancer treated with neoadjuvant PFHPert in NA-PHER2 trial (NCT02530424).
In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week 2 and surgery were significantly associated to upregulation of senescence-related genes (P = 7.7E-4 and P = 1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (P = 0.019).
Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by cotargeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>35254385</pmid><doi>10.1158/1078-0432.CCR-21-3185</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-2372-9625</orcidid><orcidid>https://orcid.org/0000-0002-6790-6267</orcidid><orcidid>https://orcid.org/0000-0003-4538-4354</orcidid><orcidid>https://orcid.org/0000-0002-6465-1078</orcidid><orcidid>https://orcid.org/0000-0003-0251-6433</orcidid><orcidid>https://orcid.org/0000-0003-1424-421X</orcidid><orcidid>https://orcid.org/0000-0003-2791-5465</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - pathology Cell Line, Tumor Cyclin-Dependent Kinase 4 - genetics Drug Resistance, Neoplasm - genetics Estrogens - metabolism Female Fulvestrant - pharmacology Fulvestrant - therapeutic use Humans Ki-67 Antigen Mechanistic Target of Rapamycin Complex 1 - genetics Receptor, ErbB-2 - metabolism Receptors, Estrogen - metabolism Translational Cancer Mechanisms and Therapy |
| title | Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer |
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