The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer
Abstract Loss of PTEN expression, via homozygous or hemizygous deletion, is common in PIK3CA mutant ER + BC tumors. We assessed reduction of PTEN protein expression on AKT inhibitor capivasertib efficacy in PIK3CA altered tumors. In PIK3CA altered, PTEN protein high models, PI3Kα and AKT inhibition...
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Nature Portfolio
2025-04-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-025-00752-9 |
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| author | Valentina Cutano Ming Li Chia Eleanor M. Wigmore Lorna Hopcroft Stuart C. Williamson Amanda L. Christie Brandon Willis James Kerr Jenny Ashforth Rhys Fox Sophie D’Arcy Lauren Bradshaw Catherine Blaker Cath Eberlein Lambert Montava-Garriga Elza C. de Bruin Susan E. Critchlow Kevin M. Brindle Simon T. Barry Susana Ros |
| author_facet | Valentina Cutano Ming Li Chia Eleanor M. Wigmore Lorna Hopcroft Stuart C. Williamson Amanda L. Christie Brandon Willis James Kerr Jenny Ashforth Rhys Fox Sophie D’Arcy Lauren Bradshaw Catherine Blaker Cath Eberlein Lambert Montava-Garriga Elza C. de Bruin Susan E. Critchlow Kevin M. Brindle Simon T. Barry Susana Ros |
| author_sort | Valentina Cutano |
| collection | DOAJ |
| description | Abstract Loss of PTEN expression, via homozygous or hemizygous deletion, is common in PIK3CA mutant ER + BC tumors. We assessed reduction of PTEN protein expression on AKT inhibitor capivasertib efficacy in PIK3CA altered tumors. In PIK3CA altered, PTEN protein high models, PI3Kα and AKT inhibition was effective, however ablation and partial PTEN expression reduction attenuated PI3Kαi but not AKTi efficacy, alone or combined with fulvestrant. Efficacy was FOXO3 dependent and associated with FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, and increased FOXM1 expression. Long term capivasertib exposure of ER+ BC cells upregulated FOXM1 expression. Downregulating FOXM1 expression reversed resistance to capivasertib, while FOXM1 overexpression reduced capivasertib efficacy. Collectively this suggests the AKT-FOXO3-FOXM1 axis plays a pivotal role in response to AKTi in ER+ breast cancer with PIK3CA mutations with and without expression of PTEN, that FOXO3 expression loss can mediate resistance, and that FOXM1 downregulation is a potential biomarker of response. |
| format | Article |
| id | doaj-art-14c2ab2c850248ca879a899d042a42f3 |
| institution | DOAJ |
| issn | 2374-4677 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj-art-14c2ab2c850248ca879a899d042a42f32025-08-20T03:15:12ZengNature Portfolionpj Breast Cancer2374-46772025-04-0111111410.1038/s41523-025-00752-9The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancerValentina Cutano0Ming Li Chia1Eleanor M. Wigmore2Lorna Hopcroft3Stuart C. Williamson4Amanda L. Christie5Brandon Willis6James Kerr7Jenny Ashforth8Rhys Fox9Sophie D’Arcy10Lauren Bradshaw11Catherine Blaker12Cath Eberlein13Lambert Montava-Garriga14Elza C. de Bruin15Susan E. Critchlow16Kevin M. Brindle17Simon T. Barry18Susana Ros19Bioscience, Early Oncology, AstraZenecaCancer Research UK Cambridge InstituteEarly Data Science, Oncology Data Science, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaDiscovery Sciences, AstraZenecaTranslational Medicine, AstraZenecaBioscience, Early Oncology, AstraZenecaCancer Research UK Cambridge InstituteBioscience, Early Oncology, AstraZenecaBioscience, Early Oncology, AstraZenecaAbstract Loss of PTEN expression, via homozygous or hemizygous deletion, is common in PIK3CA mutant ER + BC tumors. We assessed reduction of PTEN protein expression on AKT inhibitor capivasertib efficacy in PIK3CA altered tumors. In PIK3CA altered, PTEN protein high models, PI3Kα and AKT inhibition was effective, however ablation and partial PTEN expression reduction attenuated PI3Kαi but not AKTi efficacy, alone or combined with fulvestrant. Efficacy was FOXO3 dependent and associated with FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, and increased FOXM1 expression. Long term capivasertib exposure of ER+ BC cells upregulated FOXM1 expression. Downregulating FOXM1 expression reversed resistance to capivasertib, while FOXM1 overexpression reduced capivasertib efficacy. Collectively this suggests the AKT-FOXO3-FOXM1 axis plays a pivotal role in response to AKTi in ER+ breast cancer with PIK3CA mutations with and without expression of PTEN, that FOXO3 expression loss can mediate resistance, and that FOXM1 downregulation is a potential biomarker of response.https://doi.org/10.1038/s41523-025-00752-9 |
| spellingShingle | Valentina Cutano Ming Li Chia Eleanor M. Wigmore Lorna Hopcroft Stuart C. Williamson Amanda L. Christie Brandon Willis James Kerr Jenny Ashforth Rhys Fox Sophie D’Arcy Lauren Bradshaw Catherine Blaker Cath Eberlein Lambert Montava-Garriga Elza C. de Bruin Susan E. Critchlow Kevin M. Brindle Simon T. Barry Susana Ros The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer npj Breast Cancer |
| title | The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer |
| title_full | The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer |
| title_fullStr | The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer |
| title_full_unstemmed | The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer |
| title_short | The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer |
| title_sort | interplay between foxo3 and foxm1 influences sensitivity to akt inhibition in pik3ca and pik3ca pten altered estrogen receptor positive breast cancer |
| url | https://doi.org/10.1038/s41523-025-00752-9 |
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