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ER? is a target for butein-induced growth suppression in breast cancer.

ABSTRACT: Breast cancer (BCa) has the highest incidence and mortality among malignant diseases in female worldwide. BCa is frequently caused by estrogen receptor ? (ER?), a ligand-dependent receptor that highly expressed in about 70% of breast tumors. Therefore, ER? has become a well-characterized and the most effective target for treating ER?-expressing BCa (ER?⁺ BCa). However, the acquire resistance was somehow developed in patients who received current ER? signaling-targeted endocrine therapies. Hence, discovery of novel anti-estrogen/ER? strategies is urgent. In the present study, we identified butein as a potential agent for breast cancer treatment by the use of a natural product library. We showed that butein inhibits the growth of ER?⁺ BCa both in vitro and in vivo which is associated with cell cycle arrest that partially triggered by butein-induced ER? downregulation. Mechanically, butein binds to a specific pocket of ER? and promotes proteasome-mediated degradation of the receptor. Collectively, this work reveals that butein is a candidate to diminish ER? signaling which represents a potentially novel strategy for treating BCa.

SUBMITTER: Huang C

PROVIDER: S-EPMC7716169 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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ERα is a target for butein-induced growth suppression in breast cancer.

Huang Chuyi C Xia Xiaohong X He Jinchan J Liu Yuan Y Shao Zhenlong Z Hu Tumei T Yu Cuifu C Liu Xiaolin X Xu Qiong Q Liu Bin B Liu Ningning N Liao Yuning Y Huang Hongbiao H

American journal of cancer research 20201101 11

Breast cancer (BCa) has the highest incidence and mortality among malignant diseases in female worldwide. BCa is frequently caused by estrogen receptor α (ERα), a ligand-dependent receptor that highly expressed in about 70% of breast tumors. Therefore, ERα has become a well-characterized and the most effective target for treating ERα-expressing BCa (ERα<sup>+</sup> BCa). However, the acquire resistance was somehow developed in patients who received current ERα signaling-targeted endocrine therap ...[more]

PMID: 33294263

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Project description:BACKGROUND:A breast cancer susceptibility locus has been mapped to the gene encoding TOX3. Little is known regarding the expression pattern or biological role of TOX3 in breast cancer or in the mammary gland. Here we analyzed TOX3 expression in murine and human mammary glands and in molecular subtypes of breast cancer, and assessed its ability to alter the biology of breast cancer cells. METHODS:We used a cell sorting strategy, followed by quantitative real-time PCR, to study TOX3 gene expression in the mouse mammary gland. To study the expression of this nuclear protein in human mammary glands and breast tumors, we generated a rabbit monoclonal antibody specific for human TOX3. In vitro studies were performed on MCF7, BT474 and MDA-MB-231 cell lines to study the effects of TOX3 modulation on gene expression in the context of breast cancer cells. RESULTS:We found TOX3 expression in estrogen receptor-positive mammary epithelial cells, including progenitor cells. A subset of breast tumors also highly expresses TOX3, with poor outcome associated with high expression of TOX3 in luminal B breast cancers. We also demonstrate the ability of TOX3 to alter gene expression in MCF7 luminal breast cancer cells, including cancer relevant genes TFF1 and CXCR4. Knockdown of TOX3 in a luminal B breast cancer cell line that highly expresses TOX3 is associated with slower growth. Surprisingly, TOX3 is also shown to regulate TFF1 in an estrogen-independent and tamoxifen-insensitive manner. CONCLUSIONS:These results demonstrate that high expression of this protein likely plays a crucial role in breast cancer progression. This is in sharp contrast to previous studies that indicated breast cancer susceptibility is associated with lower expression of TOX3. Together, these results suggest two different roles for TOX3, one in the initiation of breast cancer, potentially related to expression of TOX3 in mammary epithelial cell progenitors, and another role for this nuclear protein in the progression of cancer. In addition, these results can begin to shed light on the reported association of TOX3 expression and breast cancer metastasis to the bone, and point to TOX3 as a novel regulator of estrogen receptor-mediated gene expression.

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ER? is a target for butein-induced growth suppression in breast cancer.

Publications

ERα is a target for butein-induced growth suppression in breast cancer.

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