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<p>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 <i>PIK3CA</i> 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.</p>

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Tamoxifen induces PI3K activation in uterine cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月22日

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  • Kirsten Kübler,
  • Agostina Nardone,
  • Shankara Anand,
  • Daniel Gurevich,
  • Jianjiong Gao,
  • Marjolein Droog,
  • Francisco Hermida-Prado,
  • Tara Akhshi,
  • Ariel Feiglin,
  • Avery S. Feit,
  • Gabriella Cohen Feit,
  • Gwen Dackus,
  • Matthew Pun,
  • Yanan Kuang,
  • Justin Cha,
  • Mendy Miller,
  • Sebastian Gregoricchio,
  • Mirthe Lanfermeijer,
  • Sten Cornelissen,
  • William J. Gibson,
  • Cloud P. Paweletz,
  • Eliezer M. Van Allen,
  • Flora E. van Leeuwen,
  • Petra M. Nederlof,
  • Quang-Dé Nguyen,
  • Marian J. E. Mourits,
  • Milan Radovich,
  • Ignaty Leshchiner,
  • Chip Stewart,
  • Ursula A. Matulonis,
  • Wilbert Zwart,
  • Yosef E. Maruvka,
  • Gad Getz,
  • Rinath Jeselsohn

摘要

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.