GPR30-mediated HMGB1 upregulation in CAFs induces autophagy and tamoxifen resistance in ER alpha-positive breast cancer cells

作者全名："Liu, Li; Liu, Shengchun; Luo, Haojun; Chen, Chenxi; Zhang, Xiaoling; He, Lin; Tu, Gang"

作者地址："[Liu, Li; Liu, Shengchun; He, Lin; Tu, Gang] Chongqing Med Univ, Dept Endocrine & Breast Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Luo, Haojun] Chongqing Med Univ, Dept Breast & Thyroid Surg, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Chen, Chenxi] Chongqing Med Univ, Dept Geriatr, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Zhang, Xiaoling] Maternal & Child Care Ctr Serv Kaizhou, Chongqing 405400, Peoples R China"

通信作者："Tu, G (corresponding author), Chongqing Med Univ, Dept Endocrine & Breast Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：AGING-US

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000669004100006

JCR分区：Q2

影响因子：5.2

年份：2021

卷号：13

期号：12

开始页：16178

结束页：16197

文献类型：Article

关键词：G-protein-coupled estrogen receptor; HMGB1; tamoxifen resistance; cancer-associated fibroblast; autophagy

摘要："Tamoxifen (TAM) resistance constitutes a challenge in managing estrogen receptor (ER)alpha+ breast cancer patients. G-protein-coupled estrogen receptor (GPR30/GPER), which reportedly initiates TAM resistance in ER alpha+/ GPR30+ breast cancers, is detected in the breast cancer microenvironment, especially cancer associated fibroblasts (CAFs). Herein, considering that GPR30 mediates transcriptional regulation in different cell backgrounds, a microarray strategy was applied in immortalized CAFs derived from primary breast cancer samples, resulting in the identification of 165 GPR30 target genes, among which HMGB1 was confirmed to be upregulated by 17-beta estradiol(E2)- and TAM-triggered GPR30 activation in CAFs. Activated GPR30 increased extracellular HMGB1 secretion by CAFs, which was reduced by blocking PI3K/AKT signaling using G15 or LY294002. GPR30-induced HMGB1 upregulation triggered MEK/ERK signaling, leading to increased autophagic behavior to protect cancer cells from TAM-induced apoptosis, mimicking the recombinant HMGB1-mediated increase in cancer cell resistance potential to TAM. MEK/ERK signaling blockage by U0126 decreased the autophagic behavior and resistance ability of cancer cells to TAM. CAF-expressed GPR30 induced TAM resistance via HMGB1 in vivo. Overall, TAM upregulated HMGB1 expression and secretion in CAFs via GPR30/PI3K/AKT signaling, and the secreted HMGB1 induced autophagy to enhance TAM resistance in MCF-7 cells in an ERK-dependent manner. Thus, targeting GPR30 and downstream cascades may be an effective strategy to attenuate the resistance of ER alpha-positive breast tumors to endocrine therapy."

基金机构："National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30872520, 81372398]"

基金资助正文："This work was supported by The National Natural Science Foundation of China (Grant. No 30872520, and 81372398) ."