Abstract 3011: Overcoming endocrine therapy resistance by drugs targeting YBX1 activation pathway in breast cancer
Authors: Shibata Tomohiro , Watari Kosuke , Kawahara Akihiko , Sudo Tomoya , Murakami Yuichi , Tokunaga Eriko , Yamashita Nami , Oki Eiji , Maehara Yoshihiko , Akiba Jun , Akagi Yoshito , Tanaka Maki , Kuwano Michihiko , Ono Mayumi 
Published: August 2019

[Background] Endocrine therapies effectively improve the outcomes of patients with estrogen receptor alpha (ERα)-positive breast cancer. However, the emergence of drug-resistant tumors is a serious challenge. Our previous studies have demonstrated that YBX1 plays pivotal roles in acquisition of endocrine therapy resistance through downregulation of ERα and upregulation of HER2/ErbB2 in breast cancer patients (Shibata et al., Cancer Res., 2017). Furthermore, many laboratories have consistently demonstrated that YBX1 expression is correlated with poor outcomes of breast cancer patients, but the mechanism underlying why YBX1 expression leads to a poor outcome has yet to be revealed. Herein, our present findings demonstrate the critical role of YBX1, and also novel approach to overcome resistance to endocrine therapy.

[Methods] We searched a TCGA database for top 500 genes that are positively or negatively correlated with YBX1 and with ESR1 in breast cancer patients. Furthermore, we established fulvestrant resistant breast cancer cell lines in which AKT/mTORC1/S6K signaling pathway is activated.

[Results] Based on our finding, YBX1 expression is consistently correlated with reduced expression of ERα and its effector genes, conferring breast cancer cells resistance to endocrine therapy. [1] The enhanced expression of YBX1 is negatively correlated with ESR1 and its effector genes in tumors, and also with poor outcomes in breast cancer patients (TCGA and patients in our hospital). [2] Enhanced expression of YBX1 and pYBX1 is closely correlated with recurrence and resistance to endocrine therapy in patients. [3] Breast cancer cells resistant to fulvestrant or tamoxifen showed markedly enhanced expression of pYBX1 and treatment with mTORC1 inhibitors almost completely overcame above resistance in vitro and in vivo. [4] Constitutive activation of YBX1 by the mutant construct induced resistance to fulvestrant, indicating that YBX1 phosphorylation is crucial for the acquired drug resistance. Enhanced expression of YBX1 and also pYBX1 is thus closely associated with endocrine therapy resistance, and also with malignant progression in breast cancer.

[Conclusion] Based on both basic and clinical findings, we will present our novel concept that activation of the oncogenic transcriptional activity by YBX1 phosphorylation is crucial for acquired resistance to endocrine therapy and also poor outcomes in breast cancer. The YBX1 activation by PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways could be useful candidates for development of overcoming drugs. We will discuss overcoming effects of mTORC1 inhibitors.

Citation Format: Tomohiro Shibata, Kosuke Watari, Akihiko Kawahara, Tomoya Sudo, Yuichi Murakami, Eriko Tokunaga, Nami Yamashita, Eiji Oki, Yoshihiko Maehara, Jun Akiba, Yoshito Akagi, Maki Tanaka, Michihiko Kuwano, Mayumi Ono. Overcoming endocrine therapy resistance by drugs targeting YBX1 activation pathway in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3011.