{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/102773"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/102773","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Necrotic cell death: A novel outcome of BHPI-hyperactivation of the anticipatory unfolded protein response","abstract":"Of the roughly 1 in 8 women that develop breast cancer in their lifetimes, 70% will have estrogen receptor a positive (ERa+) cancer. The standard of care for these cancers is endocrine therapy, including aromatase inhibitors and selective estrogen receptor modulators and degraders (SERMs and SERDs), that either block the production of estrogen or competitively inhibit the binding of estrogen to ERa. These small molecule antiestrogens work by inhibiting the proproliferative actions of estrogen but after years of treatment, many cancers recur as resistant tumors. Recently, we discovered a non-competitive modulator of ERa that works in a strikingly different way. BHPI acts through ERa to hyperactivate a lethal anticipatory unfolded protein response (UPR), hijacking a normally protective and pro-proliferative action of estrogen and ERa. We have found that BHPI effectively inhibits proliferation of and kills breast cancer cells expressing constitutive and antiestrogen resistant mutations, ERaY537S and ERaD538G, that are common in metastatic breast cancer and upregulate the UPR. Surprisingly, BHPI does not kill cancer cells through classical UPR activated, CHOP-mediated, caspase-dependent apoptosis, but rather through necrosis initiated by ATP depletion. This death pathway includes rapid swelling of ERa+ cancer cells and release of arachidonic acid, and is downstream of calcium release from the endoplasmic reticulum (EnR). Interestingly, preliminary data suggests that necrotic products released from cells treated with BHPI may act as markers of inflammation that activate immune cells. Strong and sustained activation of the anticipatory UPR leading to necrotic cell death and inflammation may represent a new strategy to target ERa+ cancers.","abstract_html":"Of the roughly 1 in 8 women that develop breast cancer in their lifetimes, 70% will have estrogen receptor a positive (ERa+) cancer. The standard of care for these cancers is endocrine therapy, including aromatase inhibitors and selective estrogen receptor modulators and degraders (SERMs and SERDs), that either block the production of estrogen or competitively inhibit the binding of estrogen to ERa. These small molecule antiestrogens work by inhibiting the proproliferative actions of estrogen but after years of treatment, many cancers recur as resistant tumors. Recently, we discovered a non-competitive modulator of ERa that works in a strikingly different way. BHPI acts through ERa to hyperactivate a lethal anticipatory unfolded protein response (UPR), hijacking a normally protective and pro-proliferative action of estrogen and ERa. We have found that BHPI effectively inhibits proliferation of and kills breast cancer cells expressing constitutive and antiestrogen resistant mutations, ERaY537S and ERaD538G, that are common in metastatic breast cancer and upregulate the UPR. Surprisingly, BHPI does not kill cancer cells through classical UPR activated, CHOP-mediated, caspase-dependent apoptosis, but rather through necrosis initiated by ATP depletion. This death pathway includes rapid swelling of ERa+ cancer cells and release of arachidonic acid, and is downstream of calcium release from the endoplasmic reticulum (EnR). Interestingly, preliminary data suggests that necrotic products released from cells treated with BHPI may act as markers of inflammation that activate immune cells. Strong and sustained activation of the anticipatory UPR leading to necrotic cell death and inflammation may represent a new strategy to target ERa+ cancers.","abstract_has_math":false,"creators":["Livezey, Mara R."],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biochemistry","degree_department":null,"school":null,"contributors":["Shapiro, David J.","Katzenellenbogen, Benita","Procko, Erik","Tajkhorshid, Emad"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-02-07T20:35:51Z","date_published":"2019-02-07T20:35:51Z","updated_at":"2026-07-22T22:24:42Z","subjects":["Estrogen receptor, cancer therapy, unfolded protein response, Necrosis"],"languages":["en"],"rights":["Copyright 2018 Mara Livezey"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/102773","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Shapiro, David J.","Katzenellenbogen, Benita","Procko, Erik","Tajkhorshid, Emad"]},{"key":"dc:creator","label":"Author","values":["Livezey, Mara R."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-02-07T20:35:51Z","2021-02-08T10:15:11Z","2018-09-05","2018-12"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biochemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Estrogen receptor, cancer therapy, unfolded protein response, Necrosis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2018 Mara Livezey"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/102773"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Of the roughly 1 in 8 women that develop breast cancer in their lifetimes, 70% will have estrogen receptor a positive (ERa+) cancer. The standard of care for these cancers is endocrine therapy, including aromatase inhibitors and selective estrogen receptor modulators and degraders (SERMs and SERDs), that either block the production of estrogen or competitively inhibit the binding of estrogen to ERa. These small molecule antiestrogens work by inhibiting the proproliferative actions of estrogen but after years of treatment, many cancers recur as resistant tumors. Recently, we discovered a non-competitive modulator of ERa that works in a strikingly different way. BHPI acts through ERa to hyperactivate a lethal anticipatory unfolded protein response (UPR), hijacking a normally protective and pro-proliferative action of estrogen and ERa. We have found that BHPI effectively inhibits proliferation of and kills breast cancer cells expressing constitutive and antiestrogen resistant mutations, ERaY537S and ERaD538G, that are common in metastatic breast cancer and upregulate the UPR. Surprisingly, BHPI does not kill cancer cells through classical UPR activated, CHOP-mediated, caspase-dependent apoptosis, but rather through necrosis initiated by ATP depletion. This death pathway includes rapid swelling of ERa+ cancer cells and release of arachidonic acid, and is downstream of calcium release from the endoplasmic reticulum (EnR). Interestingly, preliminary data suggests that necrotic products released from cells treated with BHPI may act as markers of inflammation that activate immune cells. Strong and sustained activation of the anticipatory UPR leading to necrotic cell death and inflammation may represent a new strategy to target ERa+ cancers.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2020-12-01","The student, Mara Livezey, accepted the attached license on 2018-08-30 at 16:17.","The student, Mara Livezey, submitted this Dissertation for approval on 2018-08-30 at 16:33.","This Dissertation was approved for publication on 2018-09-05 at 09:28.","DSpace SAF Submission Ingestion Package generated from Vireo submission #12990 on 2019-02-07 at 14:16:24","Made available in DSpace on 2019-02-07T20:35:51Z (GMT). No. of bitstreams: 2 LIVEZEY-DISSERTATION-2018.pdf: 10230799 bytes, checksum: cbfd6b8144e8f96e66e7e7d03037275d (MD5) LICENSE.txt: 4209 bytes, checksum: b0516d77fa087cdaa722e3d312b425a2 (MD5) Previous issue date: 2018-09-05","Embargo set by: Seth Robbins for item 109797 Lift date: 2021-02-07T20:36:09Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 109797 Lift date: 2021-02-07T20:39:46Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 109797 Lift date: 2021-02-07T20:44:35Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","U of I Only Restriction Lifted for Item 109797 on 2021-02-08T10:15:11Z."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Necrotic cell death: A novel outcome of BHPI-hyperactivation of the anticipatory unfolded protein response"]}]}],"canonical_facts":{"dc:contributor":["Shapiro, David J.","Katzenellenbogen, Benita","Procko, Erik","Tajkhorshid, Emad"],"dc:creator":["Livezey, Mara R."],"dc:date":["2019-02-07T20:35:51Z","2021-02-08T10:15:11Z","2018-09-05","2018-12"],"dc:description":["Of the roughly 1 in 8 women that develop breast cancer in their lifetimes, 70% will have estrogen receptor a positive (ERa+) cancer. The standard of care for these cancers is endocrine therapy, including aromatase inhibitors and selective estrogen receptor modulators and degraders (SERMs and SERDs), that either block the production of estrogen or competitively inhibit the binding of estrogen to ERa. These small molecule antiestrogens work by inhibiting the proproliferative actions of estrogen but after years of treatment, many cancers recur as resistant tumors. Recently, we discovered a non-competitive modulator of ERa that works in a strikingly different way. BHPI acts through ERa to hyperactivate a lethal anticipatory unfolded protein response (UPR), hijacking a normally protective and pro-proliferative action of estrogen and ERa. We have found that BHPI effectively inhibits proliferation of and kills breast cancer cells expressing constitutive and antiestrogen resistant mutations, ERaY537S and ERaD538G, that are common in metastatic breast cancer and upregulate the UPR. Surprisingly, BHPI does not kill cancer cells through classical UPR activated, CHOP-mediated, caspase-dependent apoptosis, but rather through necrosis initiated by ATP depletion. This death pathway includes rapid swelling of ERa+ cancer cells and release of arachidonic acid, and is downstream of calcium release from the endoplasmic reticulum (EnR). Interestingly, preliminary data suggests that necrotic products released from cells treated with BHPI may act as markers of inflammation that activate immune cells. Strong and sustained activation of the anticipatory UPR leading to necrotic cell death and inflammation may represent a new strategy to target ERa+ cancers.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2020-12-01","The student, Mara Livezey, accepted the attached license on 2018-08-30 at 16:17.","The student, Mara Livezey, submitted this Dissertation for approval on 2018-08-30 at 16:33.","This Dissertation was approved for publication on 2018-09-05 at 09:28.","DSpace SAF Submission Ingestion Package generated from Vireo submission #12990 on 2019-02-07 at 14:16:24","Made available in DSpace on 2019-02-07T20:35:51Z (GMT). No. of bitstreams: 2 LIVEZEY-DISSERTATION-2018.pdf: 10230799 bytes, checksum: cbfd6b8144e8f96e66e7e7d03037275d (MD5) LICENSE.txt: 4209 bytes, checksum: b0516d77fa087cdaa722e3d312b425a2 (MD5) Previous issue date: 2018-09-05","Embargo set by: Seth Robbins for item 109797 Lift date: 2021-02-07T20:36:09Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 109797 Lift date: 2021-02-07T20:39:46Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 109797 Lift date: 2021-02-07T20:44:35Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","U of I Only Restriction Lifted for Item 109797 on 2021-02-08T10:15:11Z."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/2142/102773"],"dc:language":["en"],"dc:rights":["Copyright 2018 Mara Livezey"],"dc:subject":["Estrogen receptor, cancer therapy, unfolded protein response, Necrosis"],"dc:title":["Necrotic cell death: A novel outcome of BHPI-hyperactivation of the anticipatory unfolded protein response"],"dc:type":["text"],"thesis:degree_discipline":["Biochemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:42Z"}