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<p>Co-expression of the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) contributes to breast cancer heterogeneity and therapeutic resistance. However, the molecular mechanisms promoting ER positivity within HER2+ cancers remains largely unknown. Here we show, across HER2+ transgenic mouse models the oncogenic HER2 splice variant lacking exon 16 (HER2∆16) promotes the development of aggressive luminal tumors by facilitating an ER-mediated transcriptional program which is sensitive to endocrine therapies. HER2∆16 is detected across human HER2+ breast tumors and cell lines with higher levels correlating with increased expression of ER and downstream transcriptional targets. Notably, in human cell lines HER2∆16 expression is elevated upon acquired resistance to HER2-targeted therapy and can sensitize cells to the ER-antagonist tamoxifen. Overall, these findings offer valuable insights into the role of HER2∆16 in promoting luminal cell identity and estrogen receptor positivity in breast cancer, providing a useful platform to model HER2+/ER+ disease.</p>

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HER2∆16 directs luminal cell identity and estrogen receptor signaling in HER2+ breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月15日

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  • Hailey Proud,
  • Elizabeth Podleszanski,
  • Sherif S. Attalla,
  • Ellie J. Massey,
  • Tarek Taifour,
  • Alexandra Eric,
  • Dongmei Zuo,
  • Chen Ling,
  • Alain Pacis,
  • Harvey W. Smith,
  • Vasilios Papavasiliou,
  • Virginie Sanguin-Gendreau,
  • William J. Muller

摘要

Co-expression of the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) contributes to breast cancer heterogeneity and therapeutic resistance. However, the molecular mechanisms promoting ER positivity within HER2+ cancers remains largely unknown. Here we show, across HER2+ transgenic mouse models the oncogenic HER2 splice variant lacking exon 16 (HER2∆16) promotes the development of aggressive luminal tumors by facilitating an ER-mediated transcriptional program which is sensitive to endocrine therapies. HER2∆16 is detected across human HER2+ breast tumors and cell lines with higher levels correlating with increased expression of ER and downstream transcriptional targets. Notably, in human cell lines HER2∆16 expression is elevated upon acquired resistance to HER2-targeted therapy and can sensitize cells to the ER-antagonist tamoxifen. Overall, these findings offer valuable insights into the role of HER2∆16 in promoting luminal cell identity and estrogen receptor positivity in breast cancer, providing a useful platform to model HER2+/ER+ disease.