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      Calycosin inhibits the in vitro and in vivo growth of breast cancer cells through WDR7-7-GPR30 Signaling

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          Abstract

          Background

          Clinically, breast cancer is generally classified into estrogen receptor-positive (ER+) or estrogen receptor-negative (ER−) subtypes. The phytoestrogen calycosin has been shown to inhibit the proliferation of ER+ cells, which may be mediated by a feedback loop that involves miR-375, RAS dexamethasone-induced 1 (RASD1), and ERα. However, how calycosin acts on ER− breast cancer cells remains unclear.

          Results

          Here, we show that calycosin inhibited the proliferation of both ER− (MDA-MB-468 and SKBR3) and ER+ breast cancer cells (MCF-7 and T47D) and that these inhibitory effects were associated with the up-regulation of the long non-coding RNA (lncRNA) WDR7-7. For the first time, we demonstrate that the expression of WDR7-7 is reduced in breast cancer cell lines and that the overexpression of WDR7-7 inhibits growth through a mechanism that involves G-protein coupled estrogen receptor 30 (GPR30). Meanwhile, we show that calycosin stimulated the WDR7-7-GPR30 signaling pathway in MCF-7, T47D, MDA-MB-468, and SKBR3 breast cancer cells. In contrast, in MCF10A and GPR30-deficient MDA-MB-231 cells, due to a lack of WDR7-7-GPR30 for activation, calycosin failed to inhibit cell growth. Additionally, in all four GPR30-positive breast cancer lines, calycosin decreased the phosphorylation levels of SRC, EGFR, ERK1/2 and Akt, but the inhibition of WDR7-7 blocked these changes and increased proliferation. In mice bearing MCF-7 or SKBR3 xenografts, tumor growth was inhibited by calycosin, and changes in expression the levels of WDR7-7 and GPR30 in tumor tissues were similar to those in cultured MCF-7 and SKBR3 cells.

          Conclusions

          These results suggest the possibility that calycosin inhibited the proliferation of breast cancer cells, at least partially, through WDR7-7-GPR30 signaling, which may explain why calycosin can exert inhibitory effects on ER− breast cancer.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-017-0625-y) contains supplementary material, which is available to authorized users.

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          Most cited references37

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          Estrogen receptors and human disease.

          Estrogens influence many physiological processes in mammals, including but not limited to reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen is also implicated in the development or progression of numerous diseases, which include but are not limited to various types of cancer (breast, ovarian, colorectal, prostate, endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. In many of these diseases, estrogen mediates its effects through the estrogen receptor (ER), which serves as the basis for many therapeutic interventions. This Review will describe diseases in which estrogen, through the ER, plays a role in the development or severity of disease.
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            Breast cancer statistics, 2015: Convergence of incidence rates between black and white women.

            In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including data on incidence, mortality, survival, and screening. Approximately 231,840 new cases of invasive breast cancer and 40,290 breast cancer deaths are expected to occur among US women in 2015. Breast cancer incidence rates increased among non-Hispanic black (black) and Asian/Pacific Islander women and were stable among non-Hispanic white (white), Hispanic, and American Indian/Alaska Native women from 2008 to 2012. Although white women have historically had higher incidence rates than black women, in 2012, the rates converged. Notably, during 2008 through 2012, incidence rates were significantly higher in black women compared with white women in 7 states, primarily located in the South. From 1989 to 2012, breast cancer death rates decreased by 36%, which translates to 249,000 breast cancer deaths averted in the United States over this period. This decrease in death rates was evident in all racial/ethnic groups except American Indians/Alaska Natives. However, the mortality disparity between black and white women nationwide has continued to widen; and, by 2012, death rates were 42% higher in black women than in white women. During 2003 through 2012, breast cancer death rates declined for white women in all 50 states; but, for black women, declines occurred in 27 of 30 states that had sufficient data to analyze trends. In 3 states (Mississippi, Oklahoma, and Wisconsin), breast cancer death rates in black women were stable during 2003 through 2012. Widening racial disparities in breast cancer mortality are likely to continue, at least in the short term, in view of the increasing trends in breast cancer incidence rates in black women.
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              Genetic susceptibility to triple-negative breast cancer.

              Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome-wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through the development of risk prediction models. ©2012 AACR.
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                Author and article information

                Contributors
                +86-773-5895800 , chjian80726@163.com , chenjian@glmc.edu.cn
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                2 November 2017
                2 November 2017
                2017
                : 36
                : 153
                Affiliations
                [1 ]GRID grid.443385.d, Key Laboratory of Tumor Immunology and Microenvironmental Regulation, , Guilin Medical University, ; Guilin, Guangxi 541004 China
                [2 ]GRID grid.443385.d, Department of Physiology, , Guilin Medical University, ; Guilin, Guangxi China
                [3 ]GRID grid.443385.d, Department of Breast and Thyroid Surgery, , First Affiliated Hospital of Guilin Medical University, ; Guilin, Guangxi China
                [4 ]GRID grid.443385.d, Department of Pathology and Physiopathology, , Guilin Medical University, ; Guilin, Guangxi China
                Article
                625
                10.1186/s13046-017-0625-y
                5667511
                29096683
                f33f21be-7229-460a-bb0d-292eb95eee84
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 22 August 2017
                : 23 October 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81660610, 81460403
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy
                calycosin,long non-coding rna,wdr7-7,gpr30,breast cancer
                Oncology & Radiotherapy
                calycosin, long non-coding rna, wdr7-7, gpr30, breast cancer

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