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Tamoxifen Activates PI3Kinase Signaling in Uterine Cancer and Substitutes for the lack of PIK3CA Mutations

ABSTRACT: Tamoxifen treatment in breast cancer patients increases their risk of developing uterine cancer that is more likely of poor prognosis. However, the exact mechanism leading to this increased and the worse outcomeendometrial cancer risk following tamoxifen exposure are still unknown, and effective preventive strategies are lacking. To address this question, we performed whole-exome sequencing of 21 (discovery cohort) and digital droplet PCR for 40 (validation cohort ) tamoxifen-associated uterine cancers. We identified genomic features that have been previously reported for uterine cancer, including recurrent mutations in PTEN, KRAS, TP53 and ARIDA1 and copy number alterations in the RTK and PI3K pathway. However, we also found that tamoxifen-associated uterine cancers have a substantially low frequency of PIK3CA and PIK3R1 mutations, the most prevalent mutations in non-tamoxifen-associated uterine cancers. Moreover, overall survival is significantly worse in uterine tumors without PIK3CA mutations, which could explain the observed poor prognosis in tamoxifen-associated uterine cancers . We also performed in vivo studies of normal uterine tissue and show that tamoxifen activates the PI3Kinase pathway and increases proliferation that in turn is abrogated by the PI3Kinase inhibitor, alpelisib. Together, this study uncovers the unique molecular profile of tamoxifen-associated uterine cancer and , offers mechanistic insights in the observed increase in endometrial cancer risk following tamoxifen treatment and a potential preventive approach. Moreover, we here describe for the first time a new general principle that a drug, as a side effect, can activate a pathway which would otherwise only be activated if a somatic mutation would have occurred thereby mimicking the effect of a driver mutation for cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE179647 | GEO | 2022/07/07

REPOSITORIES: GEO

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Project description:Full title: comparison of the genomic (arrayCGH) profiles of endometrial cancer with and without prior prolonged tamoxifen treatment for primary breast cancer Purpose: Tamoxifen has been a very effective treatment for breast cancer for several decades, however, at the same time increases the risk of endometrial cancer, especially after prolonged exposure. In addition, tamoxifen has been associated with a higher proportion of unfavorable uterine tumor subtypes (carcinosarcomas and serous adenocarcinomas) with worse survival. We investigated whether endometrial tumors, which developed after prolonged tamoxifen treatment for breast cancer, are genetically different from endometrial tumors without preceding tamoxifen exposure. Experimental design: Array CGH was used on archival formalin-fixed paraffin embedded (FFPE) endometrial tumors to determine genomic aberrations. We compared the genomic profiles of 52 endometrial tumors from breast cancer patients after long-term (>=2 years) tamoxifen use (endometrioid adenocarcinomas n=26, carcinosarcomas n=14 and serous adenocarcinomas n=12) with endometrial tumors from unexposed breast cancer patients (n=45). Genomic profiles were correlated with tamoxifen exposure, tumor subtypes and histopathological characteristics of the endometrial tumors. Results: The common uterine corpus cancers of the endometrioid subtype show few genomic aberrations. Tumors with many genomic aberrations were in general ER-negative. In contrast, carcinosarcomas and serous adenocarcinomas showed many aberrations, however they were indistinguishable from each other. Tumors that developed after prolonged tamoxifen use did not show more or different aberrations than unexposed tumors. This was true for all tumor subtypes. Conclusion: Endometrial carcinomas that develop after prolonged tamoxifen use can not be distinguished from non-users on basis of their tumor genomic profile. 52 endometrial tumors from breast cancer patients after long-term (>=2 years) tamoxifen use (endometrioid adenocarcinomas n=26, carcinosarcomas n=14 and serous adenocarcinomas n=12) and 45 endometrial tumors from unexposed breast cancer patients

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Tamoxifen Activates PI3Kinase Signaling in Uterine Cancer and Substitutes for the lack of PIK3CA Mutations

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