Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance

Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired r...
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Autor*in:	Kavitha Mukund [verfasserIn] Jackelyn A. Alva-Ornelas [verfasserIn] Adam L. Maddox [verfasserIn] Divya Murali [verfasserIn] Darya Veraksa [verfasserIn] Andras Saftics [verfasserIn] Jerneja Tomsic [verfasserIn] David Frankhouser [verfasserIn] Meagan Razo [verfasserIn] Tijana Jovanovic-Talisman [verfasserIn] Victoria L. Seewaldt [verfasserIn] Shankar Subramaniam [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	HER2+ breast cancer qSMLM multiomics trastuzumab resistance endogenous ligands

Übergeordnetes Werk:	In: Cancers - MDPI AG, 2010, 16(2024), 3, p 553
Übergeordnetes Werk:	volume:16 ; year:2024 ; number:3, p 553

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cancers16030553

Katalog-ID:	DOAJ094506124

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allfields	10.3390/cancers16030553 doi (DE-627)DOAJ094506124 (DE-599)DOAJec46e4f922164f8da81ba8718909b339 DE-627 ger DE-627 rakwb eng RC254-282 Kavitha Mukund verfasserin aut Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance. HER2+ breast cancer qSMLM multiomics trastuzumab resistance endogenous ligands Neoplasms. Tumors. Oncology. Including cancer and carcinogens Jackelyn A. Alva-Ornelas verfasserin aut Adam L. Maddox verfasserin aut Divya Murali verfasserin aut Darya Veraksa verfasserin aut Andras Saftics verfasserin aut Jerneja Tomsic verfasserin aut David Frankhouser verfasserin aut Meagan Razo verfasserin aut Tijana Jovanovic-Talisman verfasserin aut Victoria L. Seewaldt verfasserin aut Shankar Subramaniam verfasserin aut In Cancers MDPI AG, 2010 16(2024), 3, p 553 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:16 year:2024 number:3, p 553 https://doi.org/10.3390/cancers16030553 kostenfrei https://doaj.org/article/ec46e4f922164f8da81ba8718909b339 kostenfrei https://www.mdpi.com/2072-6694/16/3/553 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2024 3, p 553
spelling	10.3390/cancers16030553 doi (DE-627)DOAJ094506124 (DE-599)DOAJec46e4f922164f8da81ba8718909b339 DE-627 ger DE-627 rakwb eng RC254-282 Kavitha Mukund verfasserin aut Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance. HER2+ breast cancer qSMLM multiomics trastuzumab resistance endogenous ligands Neoplasms. Tumors. Oncology. Including cancer and carcinogens Jackelyn A. Alva-Ornelas verfasserin aut Adam L. Maddox verfasserin aut Divya Murali verfasserin aut Darya Veraksa verfasserin aut Andras Saftics verfasserin aut Jerneja Tomsic verfasserin aut David Frankhouser verfasserin aut Meagan Razo verfasserin aut Tijana Jovanovic-Talisman verfasserin aut Victoria L. Seewaldt verfasserin aut Shankar Subramaniam verfasserin aut In Cancers MDPI AG, 2010 16(2024), 3, p 553 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:16 year:2024 number:3, p 553 https://doi.org/10.3390/cancers16030553 kostenfrei https://doaj.org/article/ec46e4f922164f8da81ba8718909b339 kostenfrei https://www.mdpi.com/2072-6694/16/3/553 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2024 3, p 553
allfields_unstemmed	10.3390/cancers16030553 doi (DE-627)DOAJ094506124 (DE-599)DOAJec46e4f922164f8da81ba8718909b339 DE-627 ger DE-627 rakwb eng RC254-282 Kavitha Mukund verfasserin aut Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance. HER2+ breast cancer qSMLM multiomics trastuzumab resistance endogenous ligands Neoplasms. Tumors. Oncology. Including cancer and carcinogens Jackelyn A. Alva-Ornelas verfasserin aut Adam L. Maddox verfasserin aut Divya Murali verfasserin aut Darya Veraksa verfasserin aut Andras Saftics verfasserin aut Jerneja Tomsic verfasserin aut David Frankhouser verfasserin aut Meagan Razo verfasserin aut Tijana Jovanovic-Talisman verfasserin aut Victoria L. Seewaldt verfasserin aut Shankar Subramaniam verfasserin aut In Cancers MDPI AG, 2010 16(2024), 3, p 553 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:16 year:2024 number:3, p 553 https://doi.org/10.3390/cancers16030553 kostenfrei https://doaj.org/article/ec46e4f922164f8da81ba8718909b339 kostenfrei https://www.mdpi.com/2072-6694/16/3/553 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2024 3, p 553
allfieldsGer	10.3390/cancers16030553 doi (DE-627)DOAJ094506124 (DE-599)DOAJec46e4f922164f8da81ba8718909b339 DE-627 ger DE-627 rakwb eng RC254-282 Kavitha Mukund verfasserin aut Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance. HER2+ breast cancer qSMLM multiomics trastuzumab resistance endogenous ligands Neoplasms. Tumors. Oncology. Including cancer and carcinogens Jackelyn A. Alva-Ornelas verfasserin aut Adam L. Maddox verfasserin aut Divya Murali verfasserin aut Darya Veraksa verfasserin aut Andras Saftics verfasserin aut Jerneja Tomsic verfasserin aut David Frankhouser verfasserin aut Meagan Razo verfasserin aut Tijana Jovanovic-Talisman verfasserin aut Victoria L. Seewaldt verfasserin aut Shankar Subramaniam verfasserin aut In Cancers MDPI AG, 2010 16(2024), 3, p 553 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:16 year:2024 number:3, p 553 https://doi.org/10.3390/cancers16030553 kostenfrei https://doaj.org/article/ec46e4f922164f8da81ba8718909b339 kostenfrei https://www.mdpi.com/2072-6694/16/3/553 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2024 3, p 553
allfieldsSound	10.3390/cancers16030553 doi (DE-627)DOAJ094506124 (DE-599)DOAJec46e4f922164f8da81ba8718909b339 DE-627 ger DE-627 rakwb eng RC254-282 Kavitha Mukund verfasserin aut Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance. HER2+ breast cancer qSMLM multiomics trastuzumab resistance endogenous ligands Neoplasms. Tumors. Oncology. Including cancer and carcinogens Jackelyn A. Alva-Ornelas verfasserin aut Adam L. Maddox verfasserin aut Divya Murali verfasserin aut Darya Veraksa verfasserin aut Andras Saftics verfasserin aut Jerneja Tomsic verfasserin aut David Frankhouser verfasserin aut Meagan Razo verfasserin aut Tijana Jovanovic-Talisman verfasserin aut Victoria L. Seewaldt verfasserin aut Shankar Subramaniam verfasserin aut In Cancers MDPI AG, 2010 16(2024), 3, p 553 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:16 year:2024 number:3, p 553 https://doi.org/10.3390/cancers16030553 kostenfrei https://doaj.org/article/ec46e4f922164f8da81ba8718909b339 kostenfrei https://www.mdpi.com/2072-6694/16/3/553 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2024 3, p 553
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publishDateDaySort_date	2024-01-01T00:00:00Z
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callnumber-first	R - Medicine
author	Kavitha Mukund
spellingShingle	Kavitha Mukund misc RC254-282 misc HER2+ misc breast cancer misc qSMLM misc multiomics misc trastuzumab resistance misc endogenous ligands misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance
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topic_title	RC254-282 Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance HER2+ breast cancer qSMLM multiomics trastuzumab resistance endogenous ligands
topic	misc RC254-282 misc HER2+ misc breast cancer misc qSMLM misc multiomics misc trastuzumab resistance misc endogenous ligands misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc HER2+ misc breast cancer misc qSMLM misc multiomics misc trastuzumab resistance misc endogenous ligands misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC254-282 misc HER2+ misc breast cancer misc qSMLM misc multiomics misc trastuzumab resistance misc endogenous ligands misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance
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title_full	Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance
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title_sort	molecular atlas of her2+ breast cancer cells treated with endogenous ligands: temporal insights into mechanisms of trastuzumab resistance
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title_auth	Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance
abstract	Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance.
abstractGer	Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance.
abstract_unstemmed	Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance.
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title_short	Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance
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Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance

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