Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-a (ERa) and the MAP kinase, phosphoinositol 3 kinase (PI3-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ERa is four-to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERa, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI3-K and mTOR pathways through estradiolinduced binding of ERa to the IGF-I and epidermal growth factor receptors. A major question is how ERa locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ERa in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ERa, serves as the 'bus' which carries ERa to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ERa to localize in the plasma membrane. In order to abrogate growth factorinduced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.
Metastasis to other organs is the major cause of death from breast cancer. The 5-year survival rate is approximately 99% for localized breast cancer, but sharply drops to approximately 26% for patients with distant metastasis. However, there are currently no effective, targeted therapies available for treating metastatic breast cancer. Oridonin, a complex ent-kaurane diterpenoid isolated from Chinese traditional herb Rabdosia rubescens, has demonstrated great potential in the treatment of various human cancers. However, relatively low aqueous solubility and bioavailability limited its development into clinical applications. Herein, a number of novel nitrogen-enriched heterocyclic oridonin derivatives and dienone analogs such as YD0514, CYD0618, and CYD0686 have been generated from oridonin. These derivative analogs showed improved anti-proliferation effects against breast cancer cells, compared to oridonin. YD0514, CYD0618, and CYD0686 also displayed significant suppression of migration and invasion in MDA-MB-231 cell, a highly metastatic triple-negative breast cancer cell line. Furthermore, YD0514, CYD0618 and CYD0686 also inhibited the endothelial adhesion of GI101 and its derived, highly metastatic sublines, to the endothelium. We next found that YD0514, CYD0618, and CYD0686 can significantly inhibit the expression and phosphorylation of FAK and block the expression of integrin family members in those highly metastatic breast cancer cell lines. Further pathway analysis demonstrated that YD0514, CYD0618, and CYD0686 inhibited cellular motility potentially by decreasing RHOA/ROCK signaling pathway. Our findings suggest that novel oridonin-derivatives, YD0514, CYD0618, and CYD0686 have the great potential to be developed as effective therapeutics for the treatment of metastatic breast cancer. This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), and Holden Family Research Grant in BC Prevention (QS). Citation Format: Li D, Zhang Z, Ding Y, Zheng Z, Dong J, Kim H, Xu J, Chen H, Zhou J, Shen Q. Discovery of novel oridonin-derivatives for the treatment of metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-06-09.
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