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Tamoxifen enhances stemness and promotes metastasis of ER?36+ breast cancer by upregulating ALDH1A1 in cancer cells.

ABSTRACT: The 66 kDa estrogen receptor alpha (ER?66) 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 breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ER?36, a variant of ER?66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ER?36 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 ER?36 antibody. Thus, tamoxifen acts as an agonist on ER?36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ER?36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer.

SUBMITTER: Wang Q

PROVIDER: S-EPMC5835774 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Tamoxifen enhances stemness and promotes metastasis of ERα36<sup>+</sup> breast cancer by upregulating ALDH1A1 in cancer cells.

Wang Qiang Q Jiang Jun J Ying Guoguang G Xie Xiao-Qing XQ Zhang Xia X Xu Wei W Zhang Xuemin X Song Erwei E Bu Hong H Ping Yi-Fang YF Yao Xiao-Hong XH Wang Bin B Xu Shilei S Yan Ze-Xuan ZX Tai Yanhong Y Hu Baoquan B Qi Xiaowei X Wang Yan-Xia YX He Zhi-Cheng ZC Wang Yan Y Wang Ji Ming JM Cui You-Hong YH Chen Feng F Meng Kun K Wang Zhaoyi Z Bian Xiu-Wu XW

Cell research 20180202 3

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 breast cancer 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 vi ...[more]

PMID: 29393296

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Project description:BackgroundAldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. During tumor progression cancer stem cells (CSCs) have been reported to secrete angiogenic factors to orchestrate the formation of pathological angiogenesis. This vasculature can represent the source of self-renewal of CSCs and the route for further tumor spreading. The aim of the present study has been to assess whether ALDH1A1 controls the output of angiogenic factors in breast cancer cells and regulates tumor angiogenesis in a panel of in vitro and in vivo models.MethodsStemness status of breast cancer cells was evaluated by the ability to form turmorspheres in vitro. A transwell system was used to assess the angiogenic features of human umbilical vein endothelial cells (HUVEC) when co-cultured with breast cancer cells MCF-7 harboring different levels of ALDH1A1. Under these conditions, we survey endothelial proliferation, migration, tube formation and permeability. Moreover, in vivo, MCF-7 xenografts in immunodeficient mice allow to evaluate blood flow, expression of angiogenic factors and microvascular density (MVD).ResultsIn MCF-7 we observed that ALDH1A1 activity conferred stemness property and its expression correlated with an activation of angiogenic factors. In particular we observed a significant upregulation of hypoxia inducible factor-1α (HIF-1α) and proangiogenic factors, such as vascular endothelial growth factor (VEGF). High levels of ALDH1A1, through the retinoic acid pathway, were significantly associated with VEGF-mediated angiogenesis in vitro. Co-culture of HUVEC with ALDH1A1 expressing tumor cells promoted endothelial proliferation, migration, tube formation and permeability. Conversely, downregulation of ALDH1A1 in MCF-7 resulted in reduction of proangiogenic factor release/expression and impaired HUVEC angiogenic functions. In vivo, when subcutaneously implanted in immunodeficient mice, ALDH1A1 overexpressing breast tumor cells displayed a higher expression of VEGF and MVD.ConclusionIn breast tumors, ALDH1A1 expression primes a permissive microenvironment by promoting tumor angiogenesis via retinoic acid dependent mechanism. In conclusion, ALDH1A1 might be associated to progression and diffusion of breast cancer.

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Tamoxifen enhances stemness and promotes metastasis of ER?36+ breast cancer by upregulating ALDH1A1 in cancer cells.

Publications

Tamoxifen enhances stemness and promotes metastasis of ERα36<sup>+</sup> breast cancer by upregulating ALDH1A1 in cancer cells.

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Tamoxifen enhances stemness and promotes metastasis of ER?36+ breast cancer by upregulating ALDH1A1 in cancer cells.

Publications

Tamoxifen enhances stemness and promotes metastasis of ERα36&lt;sup&gt;+&lt;/sup&gt; breast cancer by upregulating ALDH1A1 in cancer cells.

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OmicsDI is part of the ELIXIR infrastructure

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Tamoxifen enhances stemness and promotes metastasis of ERα36<sup>+</sup> breast cancer by upregulating ALDH1A1 in cancer cells.