Cell Research: The Team of Prof. Xiuwu Bian, Academician of the Chinese Academy of Sciences Found Targeting ERα36 Potential To Be Novel Therapy for Tamoxifen-Resistant Breast Cancer.

 

February 6th, 2018, Beijing, China

“Tamoxifen Enhances Stemness and Promotes Metastasis of ERα36+ Breast Cancer by Upregulating ALDH1A1 in Cancer Cells” is published on Cell Research(Link:https://www.nature.com/articles/cr201815).

This study is performed by Prof. Xiuwu Bian's lab from Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University and scientists from Shenogen Pharma group.

Breast cancer is one of the most prevalent cancers and the leading cancer-related deaths in women. An estrogen receptor antagonist tamoxifen has been used for decades for the treatment of ERα66+ breast cancer. However, many patients failed after tamoxifen therapy and developed metastasis while the underlying mechanism is not clear. This study demonstrated that tamoxifen therapy was ineffective and on the contrary promoted tumor metastasis in breast cancer patients expressing ERα36, an ERα66 variant. Tamoxifen-activated ERα36 enhanced the stemness of breast cancer cells indicated by up-regulation of stem cell marker ALDH1A1.

The expression of ERα36 was examined in 1677 human breast cancer samples in five independent cohorts. In this study, we reported that tamoxifen promoted breast cancer metastasis via activation of ERα36. Our findings imply a novel mechanism by which excessive endocrine treatment leads to patient resistance in association with cancer metastasis.  This study not only reveals ERα36 can be a stratifying marker for endocrine therapy but also provides a promising therapeutic target for tamoxifen-resistant breast cancer.

Prof. Bian is the principal investigator of the clinical Trial of Class III in vitro diagnostic reagents Anti-ER-a36 Mouse Monoclonal Antibody(IHC). Under the leadership of Prof. Bian, the Diagnostic Program team made significant progress in the development of this diagnostic product. This multi-sites clinical trial has enrolled nearly 1000 clinical breast cancer patients as of today.

The above research based on ERa36 targeting drug discovery and development and breast cancer diagnosis provides important clinical evidence for Tamoxifen- resistant breast cancer therapy.

ABSTRACT

The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breastcancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1).

Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer.

 

 

 

About Shenogen

Shenogen Pharma Group is a drug discovery and development company based in Beijing, China, that dedicated the development of first-in-class therapeutics for cancer treatment. We possess robust intellectual property rights around a novel membrane-bound estrogen receptor, ER-alpha 36, which is related to tumor metastasis. Under the motto of “Better Medicine, Better Life” and a seasoned management team, together with our partners, Shenogen has developed an impressive product pipeline. Our pipeline consists of novel small molecule and antibody therapeutics for cancer treatment which includes liver cancer, breast cancer, other solid tumors and leukemia. Our lead molecule, icaritin, is currently in Ph III clinical trial for treatment of advanced hepatocellular carcinoma.

(For more information, please visit www.shenogen.com.cn.)

 

 

 


2018年02月06日

The Team of Prof. Xiuwu Bian, Academician of the Chinese Academy of Sciences Found Targeting ERα36 Potential To Be Novel Therapy for Tamoxifen-Resistant Breast Cancer

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