Abstract P4-01-15: Eribulin treatment for hormone receptor positive breast cancer cells with resistant to endocrine therapy promotes re-expression of estrogen receptor
Authors: Wataru Goto, Shinichiro Kashiwagi, Misato Fujioka, Sae Ishihara, Yuka Asano, Tamami Morisaki, Satoru Noda, Tsutomu Takashima, Masaichi Ohira, Kosei Hirakawa
Journal: Cancer Research (2022)

Abstract Background: The development of resistance to endocrine therapy appears to have become a major clinical problem of hormone receptor (HR) positive breast cancer. Drug resistance is associated with changes of the tumor microenvironment due to tumor hypoxia. Eribulin, a nontaxane, synthetic microtuble dynamics inhibitor, induces G2/M cell cycle arrest. Interestingly, it also has some unique anticancer effects in breast cancer cells, such as improvement of tumor perfusion and hypoxia. In this study, we investigated the effect of eribulin for endocrine therapy resistant breast cancer. Materials and Methods: We established hypoxia resistant HR positive/human epithelial growth receptor 2 (HER2) negative breast cancer cell lines, via continuous culturing in hypoxic environment. Parental and hypoxia resistant cell lines were treated with eribulin, followed by estrogen receptor (ER), epithelial-mesenchymal transition (EMT) and hypoxia related gene and protein expression changes in each surviving cells by quantitative real-time polymerase chain reaction (qPCR) and western blot, respectively. In addition, proliferation assay was conducted in these breast cancer cell lines treated with tamoxifen alone and tamoxifen plus eribulin. For the in vivo experiment, we produced subcutaneous xenografts of each cell lines. We treated these tumors with tamoxifen alone and tamoxifen plus eribulin, and analyzed their growth activity and protein expression by immunohistochemical study of surgically resected tissues. Results: Though parental HR positive/HER2 negative breast cancer cell lines displayed an epithelial-like cuboidal phenotype, hypoxia resistant cell lines displayed a mesenchymal-like spindle-shaped phenotype. In addition, hypoxia resistant cell lines significantly decreased the expression of epithelial and ER related markers, and exhibited a higher level of resistance to tamoxifen treatment. On the other hand, eribulin treatment for hypoxia resistant cell lines increased epithelial and ER related gene and protein expressions, and enhanced the anticancer effect of tamoxifen. In in vivo xenograft models, eribulin treatment for hypoxia resistant tumor with resistance to tamoxifen induced re-expression of ER. Also, hypoxia resistant tumor after administration of eribulin became effective with tamoxifen treatment. Conclusions: Eribulin improve the tumor microenvironment changed by hypoxia, and induce re-expression of ER in hypoxia resistant breast cancer cells. Eribulin treatment for HR positive breast cancer with resistance to endocrine therapy makes possibility of re-administration of endocrine therapy. Citation Format: Wataru Goto, Shinichiro Kashiwagi, Misato Fujioka, Sae Ishihara, Yuka Asano, Tamami Morisaki, Satoru Noda, Tsutomu Takashima, Masaichi Ohira, Kosei Hirakawa. Eribulin treatment for hormone receptor positive breast cancer cells with resistant to endocrine therapy promotes re-expression of estrogen receptor [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-15.