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Tamoxifen induces PI3K activation in uterine cancer
Kirsten Kübler1,2,3,4,5,6, Agostina Nardone7, Shankara Anand8
1Broad Institute of MIT and Harvard, Cambridge, MA, USA. kirsten.kuebler@bih-charite.de.
Abstract:
Mutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors. In vivo, tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue, potentially eliminating the selective benefit of PI3K-activating mutations in tamoxifen-associated uterine cancer. Together, we present a unique pathway of therapy-associated carcinogenesis in which tamoxifen-induced activation of the PI3K pathway acts as a non-genetic driver event, contributing to the multistep model of uterine carcinogenesis. While this PI3K mechanism is specific to tamoxifen-associated uterine cancer, the concept of treatment-induced signaling events may have broader applicability to other routes of tumorigenesis.
Insights
Tamoxifen therapy rarely causes uterine cancer, but the genetic cause was unknown. This study reveals tamoxifen activates a key cancer pathway, acting as a non-genetic driver in uterine tumor development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Therapy-associated secondary neoplasms are a known complication of cancer treatment.
- Tamoxifen therapy is linked to secondary uterine cancers, but the underlying genetic mechanisms are unclear.
Purpose of the Study:
- To investigate the genetic mechanisms of tamoxifen-driven uterine tumorigenesis.
- To explore the role of PIK3CA mutations and PI3K signaling in tamoxifen-associated uterine cancer.
Main Methods:
- Comparative analysis of PIK3CA mutation frequency in tamoxifen-associated versus de novo uterine cancers.
- In vivo studies using mouse models to assess tamoxifen-induced estrogen receptor stimulation and PI3K signaling activation in uterine tissue.
Main Results:
- Oncogenic PIK3CA mutations are significantly less frequent in tamoxifen-associated uterine tumors compared to de novo uterine cancers.
- Tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue.
Conclusions:
- Tamoxifen-induced PI3K pathway activation acts as a non-genetic driver event in uterine carcinogenesis.
- This PI3K pathway activation may eliminate the selective advantage of PI3K-activating mutations in tamoxifen-associated uterine cancer.
- The concept of treatment-induced signaling events may be broadly applicable to other types of tumorigenesis.
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