Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer

Swaathi Jayaraman, Xiaonan Hou, Mary J. Kuffel, Vera J. Suman, Tanya L. Hoskin, Kathryn E. Reinicke, David G. Monroe, Krishna R. Kalari, Xiaojia Tang, Megan A. Zeldenrust, Jingfei Cheng, Elizabeth S. Bruinsma, Sarah A. Buhrow, Renee M. McGovern, Stephanie L. Safgren, Chad A. Walden, Jodi M. Carter, Joel M. Reid, James N. Ingle, Matthew M. AmesJohn R. Hawse, Matthew P. Goetz

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR). Methods: MCF7AC1 tumor-bearing mice were randomized to control (no drug), letrozole (10 μg/day), tamoxifen (500 μg/day), or Z-endoxifen (25 and 75 mg/kg). Treatment in the letrozole arm was continued until resistance developed. MCF7LR tumor-bearing mice were then randomized to Z-endoxifen (50 mg/kg) or tamoxifen for 4 weeks and tumors harvested for microarray and immunohistochemistry analysis. The antitumor activity of Z-endoxifen in the MCF7LR tumors was further compared in a second in vivo study with exemestane, exemestane plus everolimus, and fulvestrant. Results: In the MCF7AC1 tumors, both Z-endoxifen doses were significantly superior to control and tamoxifen in reducing tumor volumes at 4 weeks. Additionally, the 75 mg/kg Z-endoxifen dose was additionally superior to letrozole. Prolonged letrozole exposure resulted in resistance at 25 weeks. In MCF7LR tumor-bearing mice, Z-endoxifen significantly reduced tumor volumes compared to tamoxifen, letrozole, and exemestane, with no significant differences compared to exemestane plus everolimus and fulvestrant. Additionally, compared to tamoxifen, Z-endoxifen markedly inhibited ERα target genes, Ki67 and Akt expression in vivo. Conclusion: In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.

Original languageEnglish (US)
Article number51
JournalBreast Cancer Research
Issue number1
StatePublished - May 19 2020


  • AI-resistant and AI-sensitive ER+ breast cancer
  • Estrogen-regulated genes
  • Signaling kinase
  • Tamoxifen
  • Tumor growth in vivo
  • Z-endoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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