Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action
Aromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole versus exemestane, we identified a single nucleotide polymorp...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2020-08-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.137571 |
| _version_ | 1823938535013482496 |
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| author | Junmei Cairns James N. Ingle Tanda M. Dudenkov Krishna R. Kalari Erin E. Carlson Jie Na Aman U. Buzdar Mark E. Robson Matthew J. Ellis Paul E. Goss Lois E. Shepherd Barbara Goodnature Matthew P. Goetz Richard M. Weinshilboum Hu Li Mehrab Ghanat Bari Liewei Wang |
| author_facet | Junmei Cairns James N. Ingle Tanda M. Dudenkov Krishna R. Kalari Erin E. Carlson Jie Na Aman U. Buzdar Mark E. Robson Matthew J. Ellis Paul E. Goss Lois E. Shepherd Barbara Goodnature Matthew P. Goetz Richard M. Weinshilboum Hu Li Mehrab Ghanat Bari Liewei Wang |
| author_sort | Junmei Cairns |
| collection | DOAJ |
| description | Aromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole versus exemestane, we identified a single nucleotide polymorphism (SNP) in CUB And Sushi multiple domains 1 (CSMD1) associated with breast cancer–free interval, with the variant allele associated with fewer distant recurrences. Mechanistically, CSMD1 regulates CYP19 expression in an SNP- and drug-dependent fashion, and this regulation is different among 3 AIs: anastrozole, exemestane, and letrozole. Overexpression of CSMD1 sensitized AI-resistant cells to anastrozole but not to the other 2 AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane sensitivity. Anastrozole degrades estrogen receptor α (ERα), especially in the presence of estradiol (E2). ER+ breast cancer organoids and AI- or fulvestrant-resistant breast cancer cells were more sensitive to anastrozole plus E2 than to AI alone. Our findings suggest that the CSMD1 SNP might help to predict AI response, and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers. |
| first_indexed | 2024-12-17T02:46:50Z |
| format | Article |
| id | doaj.art-d318692f04d14855bf3070f9a33fe2ab |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-17T02:46:50Z |
| publishDate | 2020-08-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d318692f04d14855bf3070f9a33fe2ab2022-12-21T22:06:33ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-08-01516Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole actionJunmei CairnsJames N. IngleTanda M. DudenkovKrishna R. KalariErin E. CarlsonJie NaAman U. BuzdarMark E. RobsonMatthew J. EllisPaul E. GossLois E. ShepherdBarbara GoodnatureMatthew P. GoetzRichard M. WeinshilboumHu LiMehrab Ghanat BariLiewei WangAromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole versus exemestane, we identified a single nucleotide polymorphism (SNP) in CUB And Sushi multiple domains 1 (CSMD1) associated with breast cancer–free interval, with the variant allele associated with fewer distant recurrences. Mechanistically, CSMD1 regulates CYP19 expression in an SNP- and drug-dependent fashion, and this regulation is different among 3 AIs: anastrozole, exemestane, and letrozole. Overexpression of CSMD1 sensitized AI-resistant cells to anastrozole but not to the other 2 AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane sensitivity. Anastrozole degrades estrogen receptor α (ERα), especially in the presence of estradiol (E2). ER+ breast cancer organoids and AI- or fulvestrant-resistant breast cancer cells were more sensitive to anastrozole plus E2 than to AI alone. Our findings suggest that the CSMD1 SNP might help to predict AI response, and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers.https://doi.org/10.1172/jci.insight.137571OncologyTherapeutics |
| spellingShingle | Junmei Cairns James N. Ingle Tanda M. Dudenkov Krishna R. Kalari Erin E. Carlson Jie Na Aman U. Buzdar Mark E. Robson Matthew J. Ellis Paul E. Goss Lois E. Shepherd Barbara Goodnature Matthew P. Goetz Richard M. Weinshilboum Hu Li Mehrab Ghanat Bari Liewei Wang Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action JCI Insight Oncology Therapeutics |
| title | Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action |
| title_full | Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action |
| title_fullStr | Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action |
| title_full_unstemmed | Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action |
| title_short | Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action |
| title_sort | pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/jci.insight.137571 |
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