Cargando…
Functional Characterization of Circulating Tumor Cells (CTCs) from Metastatic ER+/HER2− Breast Cancer Reveals Dependence on HER2 and FOXM1 for Endocrine Therapy Resistance and Tumor Cell Survival: Implications for Treatment of ER+/HER2− Breast Cancer
SIMPLE SUMMARY: Acquired endocrine resistance and late recurrence in patients with ER+/HER2− breast cancer are complex and not fully understood. Here, we evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2− breast cancer patient who initially responded but...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070196/ https://www.ncbi.nlm.nih.gov/pubmed/33920089 http://dx.doi.org/10.3390/cancers13081810 |
_version_ | 1783683413965799424 |
---|---|
author | Roßwag, Sven Cotarelo, Cristina L. Pantel, Klaus Riethdorf, Sabine Sleeman, Jonathan P. Schmidt, Marcus Thaler, Sonja |
author_facet | Roßwag, Sven Cotarelo, Cristina L. Pantel, Klaus Riethdorf, Sabine Sleeman, Jonathan P. Schmidt, Marcus Thaler, Sonja |
author_sort | Roßwag, Sven |
collection | PubMed |
description | SIMPLE SUMMARY: Acquired endocrine resistance and late recurrence in patients with ER+/HER2− breast cancer are complex and not fully understood. Here, we evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2− breast cancer patient who initially responded but later progressed under endocrine treatment. We found a switch from ERα-dependent to HER2-dependent and ERα-independent expression of FOXM1, which may enable disseminated ER+/HER2− cells to re-initiate tumor cell growth and metastasis formation in the presence of endocrine treatment. We found that NFkB signaling sustains HER2 and FOXM1 expression in CTCs in the presence of ERα inhibitors suggesting that NFkB and FOXM1 might be an efficient therapeutic approach to prevent late recurrence and to treat endocrine resistance. Collectively our data show that CTCs from patients with endocrine resistance allow mechanisms of acquired endocrine resistance to be delineated, and can be used to test potential drug regimens for combatting resistance. ABSTRACT: Mechanisms of acquired endocrine resistance and late recurrence in patients with ER+/HER2− breast cancer are complex and not fully understood. Here, we evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2− breast cancer patient who initially responded but later progressed under endocrine treatment. We found a switch from ERα-dependent to HER2-dependent and ERα-independent expression of FOXM1, which may enable disseminated ER+/HER2− cells to re-initiate tumor cell growth and metastasis formation in the presence of endocrine treatment. Our results also suggest a role for HER2 in resistance, even in ER+ breast cancer cells that have neither HER2 amplification nor activating HER2 mutations. We found that NFkB signaling sustains HER2 and FOXM1 expression in CTCs in the presence of ERα inhibitors. Inhibition of NFkB signaling blocked expression of HER2 and FOXM1 in the CTCs, and induced apoptosis. Thus, targeting of NFkB and FOXM1 might be an efficient therapeutic approach to prevent late recurrence and to treat endocrine resistance. Collectively our data show that CTCs from patients with endocrine resistance allow mechanisms of acquired endocrine resistance to be delineated, and can be used to test potential drug regimens for combatting resistance. |
format | Online Article Text |
id | pubmed-8070196 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80701962021-04-26 Functional Characterization of Circulating Tumor Cells (CTCs) from Metastatic ER+/HER2− Breast Cancer Reveals Dependence on HER2 and FOXM1 for Endocrine Therapy Resistance and Tumor Cell Survival: Implications for Treatment of ER+/HER2− Breast Cancer Roßwag, Sven Cotarelo, Cristina L. Pantel, Klaus Riethdorf, Sabine Sleeman, Jonathan P. Schmidt, Marcus Thaler, Sonja Cancers (Basel) Article SIMPLE SUMMARY: Acquired endocrine resistance and late recurrence in patients with ER+/HER2− breast cancer are complex and not fully understood. Here, we evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2− breast cancer patient who initially responded but later progressed under endocrine treatment. We found a switch from ERα-dependent to HER2-dependent and ERα-independent expression of FOXM1, which may enable disseminated ER+/HER2− cells to re-initiate tumor cell growth and metastasis formation in the presence of endocrine treatment. We found that NFkB signaling sustains HER2 and FOXM1 expression in CTCs in the presence of ERα inhibitors suggesting that NFkB and FOXM1 might be an efficient therapeutic approach to prevent late recurrence and to treat endocrine resistance. Collectively our data show that CTCs from patients with endocrine resistance allow mechanisms of acquired endocrine resistance to be delineated, and can be used to test potential drug regimens for combatting resistance. ABSTRACT: Mechanisms of acquired endocrine resistance and late recurrence in patients with ER+/HER2− breast cancer are complex and not fully understood. Here, we evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2− breast cancer patient who initially responded but later progressed under endocrine treatment. We found a switch from ERα-dependent to HER2-dependent and ERα-independent expression of FOXM1, which may enable disseminated ER+/HER2− cells to re-initiate tumor cell growth and metastasis formation in the presence of endocrine treatment. Our results also suggest a role for HER2 in resistance, even in ER+ breast cancer cells that have neither HER2 amplification nor activating HER2 mutations. We found that NFkB signaling sustains HER2 and FOXM1 expression in CTCs in the presence of ERα inhibitors. Inhibition of NFkB signaling blocked expression of HER2 and FOXM1 in the CTCs, and induced apoptosis. Thus, targeting of NFkB and FOXM1 might be an efficient therapeutic approach to prevent late recurrence and to treat endocrine resistance. Collectively our data show that CTCs from patients with endocrine resistance allow mechanisms of acquired endocrine resistance to be delineated, and can be used to test potential drug regimens for combatting resistance. MDPI 2021-04-10 /pmc/articles/PMC8070196/ /pubmed/33920089 http://dx.doi.org/10.3390/cancers13081810 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Roßwag, Sven Cotarelo, Cristina L. Pantel, Klaus Riethdorf, Sabine Sleeman, Jonathan P. Schmidt, Marcus Thaler, Sonja Functional Characterization of Circulating Tumor Cells (CTCs) from Metastatic ER+/HER2− Breast Cancer Reveals Dependence on HER2 and FOXM1 for Endocrine Therapy Resistance and Tumor Cell Survival: Implications for Treatment of ER+/HER2− Breast Cancer |
title | Functional Characterization of Circulating Tumor Cells (CTCs) from Metastatic ER+/HER2− Breast Cancer Reveals Dependence on HER2 and FOXM1 for Endocrine Therapy Resistance and Tumor Cell Survival: Implications for Treatment of ER+/HER2− Breast Cancer |
title_full | Functional Characterization of Circulating Tumor Cells (CTCs) from Metastatic ER+/HER2− Breast Cancer Reveals Dependence on HER2 and FOXM1 for Endocrine Therapy Resistance and Tumor Cell Survival: Implications for Treatment of ER+/HER2− Breast Cancer |
title_fullStr | Functional Characterization of Circulating Tumor Cells (CTCs) from Metastatic ER+/HER2− Breast Cancer Reveals Dependence on HER2 and FOXM1 for Endocrine Therapy Resistance and Tumor Cell Survival: Implications for Treatment of ER+/HER2− Breast Cancer |
title_full_unstemmed | Functional Characterization of Circulating Tumor Cells (CTCs) from Metastatic ER+/HER2− Breast Cancer Reveals Dependence on HER2 and FOXM1 for Endocrine Therapy Resistance and Tumor Cell Survival: Implications for Treatment of ER+/HER2− Breast Cancer |
title_short | Functional Characterization of Circulating Tumor Cells (CTCs) from Metastatic ER+/HER2− Breast Cancer Reveals Dependence on HER2 and FOXM1 for Endocrine Therapy Resistance and Tumor Cell Survival: Implications for Treatment of ER+/HER2− Breast Cancer |
title_sort | functional characterization of circulating tumor cells (ctcs) from metastatic er+/her2− breast cancer reveals dependence on her2 and foxm1 for endocrine therapy resistance and tumor cell survival: implications for treatment of er+/her2− breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070196/ https://www.ncbi.nlm.nih.gov/pubmed/33920089 http://dx.doi.org/10.3390/cancers13081810 |
work_keys_str_mv | AT roßwagsven functionalcharacterizationofcirculatingtumorcellsctcsfrommetastaticerher2breastcancerrevealsdependenceonher2andfoxm1forendocrinetherapyresistanceandtumorcellsurvivalimplicationsfortreatmentoferher2breastcancer AT cotarelocristinal functionalcharacterizationofcirculatingtumorcellsctcsfrommetastaticerher2breastcancerrevealsdependenceonher2andfoxm1forendocrinetherapyresistanceandtumorcellsurvivalimplicationsfortreatmentoferher2breastcancer AT pantelklaus functionalcharacterizationofcirculatingtumorcellsctcsfrommetastaticerher2breastcancerrevealsdependenceonher2andfoxm1forendocrinetherapyresistanceandtumorcellsurvivalimplicationsfortreatmentoferher2breastcancer AT riethdorfsabine functionalcharacterizationofcirculatingtumorcellsctcsfrommetastaticerher2breastcancerrevealsdependenceonher2andfoxm1forendocrinetherapyresistanceandtumorcellsurvivalimplicationsfortreatmentoferher2breastcancer AT sleemanjonathanp functionalcharacterizationofcirculatingtumorcellsctcsfrommetastaticerher2breastcancerrevealsdependenceonher2andfoxm1forendocrinetherapyresistanceandtumorcellsurvivalimplicationsfortreatmentoferher2breastcancer AT schmidtmarcus functionalcharacterizationofcirculatingtumorcellsctcsfrommetastaticerher2breastcancerrevealsdependenceonher2andfoxm1forendocrinetherapyresistanceandtumorcellsurvivalimplicationsfortreatmentoferher2breastcancer AT thalersonja functionalcharacterizationofcirculatingtumorcellsctcsfrommetastaticerher2breastcancerrevealsdependenceonher2andfoxm1forendocrinetherapyresistanceandtumorcellsurvivalimplicationsfortreatmentoferher2breastcancer |