Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex
The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2023-09, Vol.83 (17), p.2938-2951 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | Nyquist, Michael D Coleman, Ilsa M Lucas, Jared M Li, Dapei Hanratty, Brian Meade, Hannah Mostaghel, Elahe A Plymate, Stephen R Corey, Eva Haffner, Michael C Nelson, Peter S |
| description | The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA) results in growth repression and improved outcomes in subsets of patients with prostate cancer. A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses indicated that the dimerization partner, RB-like, E2F, and multivulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment, whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.
Determining the molecular pathways by which supraphysiological androgens promote growth arrest and treatment responses in prostate cancer provides opportunities for biomarker-selected clinical trials and the development of strategies to augment responses. |
| doi_str_mv | 10.1158/0008-5472.CAN-22-2613 |
| format | Article |
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Determining the molecular pathways by which supraphysiological androgens promote growth arrest and treatment responses in prostate cancer provides opportunities for biomarker-selected clinical trials and the development of strategies to augment responses.</description><identifier>ISSN: 0008-5472</identifier><identifier>ISSN: 1538-7445</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-22-2613</identifier><identifier>PMID: 37352376</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Androgens - metabolism ; Cell Line, Tumor ; Humans ; Male ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - metabolism ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; Receptors, Androgen - genetics ; Receptors, Androgen - metabolism ; Signal Transduction ; Translational Cancer Biology</subject><ispartof>Cancer research (Chicago, Ill.), 2023-09, Vol.83 (17), p.2938-2951</ispartof><rights>2023 The Authors; Published by the American Association for Cancer Research.</rights><rights>2023 The Authors; Published by the American Association for Cancer Research 2023 American Association for Cancer Research</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-72430cdd1b6ee3b005bd7294d5b7c28821131ec2acf5bdd0d3df53d25715d2243</citedby><cites>FETCH-LOGICAL-c412t-72430cdd1b6ee3b005bd7294d5b7c28821131ec2acf5bdd0d3df53d25715d2243</cites><orcidid>0000-0003-4580-649X ; 0000-0002-7597-6943 ; 0000-0003-2743-8435 ; 0000-0001-8169-8743 ; 0000-0002-5451-5726 ; 0009-0003-9531-3658 ; 0009-0008-2037-1809 ; 0000-0002-9244-3807 ; 0000-0003-0809-6425 ; 0000-0002-1483-7202 ; 0000-0002-7769-2864</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/37352376$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nyquist, Michael D</creatorcontrib><creatorcontrib>Coleman, Ilsa M</creatorcontrib><creatorcontrib>Lucas, Jared M</creatorcontrib><creatorcontrib>Li, Dapei</creatorcontrib><creatorcontrib>Hanratty, Brian</creatorcontrib><creatorcontrib>Meade, Hannah</creatorcontrib><creatorcontrib>Mostaghel, Elahe A</creatorcontrib><creatorcontrib>Plymate, Stephen R</creatorcontrib><creatorcontrib>Corey, Eva</creatorcontrib><creatorcontrib>Haffner, Michael C</creatorcontrib><creatorcontrib>Nelson, Peter S</creatorcontrib><title>Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA) results in growth repression and improved outcomes in subsets of patients with prostate cancer. A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses indicated that the dimerization partner, RB-like, E2F, and multivulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment, whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.
Determining the molecular pathways by which supraphysiological androgens promote growth arrest and treatment responses in prostate cancer provides opportunities for biomarker-selected clinical trials and the development of strategies to augment responses.</description><subject>Androgens - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Humans</subject><subject>Male</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Receptors, Androgen - genetics</subject><subject>Receptors, Androgen - metabolism</subject><subject>Signal Transduction</subject><subject>Translational Cancer Biology</subject><issn>0008-5472</issn><issn>1538-7445</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1u1DAUhS0EotPCI4C8ZJPin3iSWaEolB-pBVTKgpXl2DcToyRObWfEPErfFofpjGBl2fc7x8c-CL2i5JJSUb4lhJSZyAt2WVdfMsYytqb8CVpRwcusyHPxFK1OzBk6D-FX2gpKxHN0xgsuGC_WK_TwfZ68mrp9sK53W6tVj6vReLeFMeBv3g0uAo4d4Lt5cB4nfPIQgt0BrnS0Oxv32LV_iaMO34KGKSY6dt7N2w7rm591Oj0o3YjVaBbIzzYOMMajwfvbq-oG126Yevj9Aj1rVR_g5eN6gX58uLqrP2XXXz9-rqvrTOeUxaxgOSfaGNqsAXiTntiYgm1yI5pCs7JklHIKmindpokhhptWcMNEQYVhSXyB3h18p7kZwOiUx6teTt4Oyu-lU1b-PxltJ7duJylJP0sJSQ5vHh28u58hRDnYoKHv1QhuDpKVKQ8rNhuaUHFAtXcheGhP91Ail17l0plcOpOpV8mYXHpNutf_hjypjkXyP-5zopE</recordid><startdate>20230901</startdate><enddate>20230901</enddate><creator>Nyquist, Michael D</creator><creator>Coleman, Ilsa M</creator><creator>Lucas, Jared M</creator><creator>Li, Dapei</creator><creator>Hanratty, Brian</creator><creator>Meade, Hannah</creator><creator>Mostaghel, Elahe A</creator><creator>Plymate, Stephen R</creator><creator>Corey, Eva</creator><creator>Haffner, Michael C</creator><creator>Nelson, Peter S</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/0000-0003-4580-649X</orcidid><orcidid>https://orcid.org/0000-0002-7597-6943</orcidid><orcidid>https://orcid.org/0000-0003-2743-8435</orcidid><orcidid>https://orcid.org/0000-0001-8169-8743</orcidid><orcidid>https://orcid.org/0000-0002-5451-5726</orcidid><orcidid>https://orcid.org/0009-0003-9531-3658</orcidid><orcidid>https://orcid.org/0009-0008-2037-1809</orcidid><orcidid>https://orcid.org/0000-0002-9244-3807</orcidid><orcidid>https://orcid.org/0000-0003-0809-6425</orcidid><orcidid>https://orcid.org/0000-0002-1483-7202</orcidid><orcidid>https://orcid.org/0000-0002-7769-2864</orcidid></search><sort><creationdate>20230901</creationdate><title>Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex</title><author>Nyquist, Michael D ; Coleman, Ilsa M ; Lucas, Jared M ; Li, Dapei ; Hanratty, Brian ; Meade, Hannah ; Mostaghel, Elahe A ; Plymate, Stephen R ; Corey, Eva ; Haffner, Michael C ; Nelson, Peter S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-72430cdd1b6ee3b005bd7294d5b7c28821131ec2acf5bdd0d3df53d25715d2243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Androgens - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Humans</topic><topic>Male</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>Receptors, Androgen - genetics</topic><topic>Receptors, Androgen - metabolism</topic><topic>Signal Transduction</topic><topic>Translational Cancer Biology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nyquist, Michael D</creatorcontrib><creatorcontrib>Coleman, Ilsa M</creatorcontrib><creatorcontrib>Lucas, Jared M</creatorcontrib><creatorcontrib>Li, Dapei</creatorcontrib><creatorcontrib>Hanratty, Brian</creatorcontrib><creatorcontrib>Meade, Hannah</creatorcontrib><creatorcontrib>Mostaghel, Elahe A</creatorcontrib><creatorcontrib>Plymate, Stephen R</creatorcontrib><creatorcontrib>Corey, Eva</creatorcontrib><creatorcontrib>Haffner, Michael C</creatorcontrib><creatorcontrib>Nelson, Peter S</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>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nyquist, Michael D</au><au>Coleman, Ilsa M</au><au>Lucas, Jared M</au><au>Li, Dapei</au><au>Hanratty, Brian</au><au>Meade, Hannah</au><au>Mostaghel, Elahe A</au><au>Plymate, Stephen R</au><au>Corey, Eva</au><au>Haffner, Michael C</au><au>Nelson, Peter S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2023-09-01</date><risdate>2023</risdate><volume>83</volume><issue>17</issue><spage>2938</spage><epage>2951</epage><pages>2938-2951</pages><issn>0008-5472</issn><issn>1538-7445</issn><eissn>1538-7445</eissn><abstract>The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA) results in growth repression and improved outcomes in subsets of patients with prostate cancer. A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses indicated that the dimerization partner, RB-like, E2F, and multivulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment, whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.
Determining the molecular pathways by which supraphysiological androgens promote growth arrest and treatment responses in prostate cancer provides opportunities for biomarker-selected clinical trials and the development of strategies to augment responses.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>37352376</pmid><doi>10.1158/0008-5472.CAN-22-2613</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-4580-649X</orcidid><orcidid>https://orcid.org/0000-0002-7597-6943</orcidid><orcidid>https://orcid.org/0000-0003-2743-8435</orcidid><orcidid>https://orcid.org/0000-0001-8169-8743</orcidid><orcidid>https://orcid.org/0000-0002-5451-5726</orcidid><orcidid>https://orcid.org/0009-0003-9531-3658</orcidid><orcidid>https://orcid.org/0009-0008-2037-1809</orcidid><orcidid>https://orcid.org/0000-0002-9244-3807</orcidid><orcidid>https://orcid.org/0000-0003-0809-6425</orcidid><orcidid>https://orcid.org/0000-0002-1483-7202</orcidid><orcidid>https://orcid.org/0000-0002-7769-2864</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Androgens - metabolism Cell Line, Tumor Humans Male Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Receptors, Androgen - genetics Receptors, Androgen - metabolism Signal Transduction Translational Cancer Biology |
| title | Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex |
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