乳腺癌抗雌激素治疗耐药的分子靶点

Currently, the therapeutic options for the treatment of hormone refractory breast cancer remain limited. The mechanism of acquired tamoxifen resistance remains poorly understood and may be mediated by multiple pathways. We previously identified a Breast Cancer Specific Gene BCSG1 also named as synuclein gamma (SNCG). SNCG is a new unfavorable prognostic marker for breast cancer progression and a potential target for breast cancer treatment. SNCG, acting as a tumor specific chaperone, regulates many pathways, including stimulation of ERα signaling and hormone-dependent growth and tumorigenesis. ER-α36, a membrane-bound new variant of estrogen receptor α(ERα), can induce non-genomic membrane-initiated estrogen signaling (MIES). Recently, an association between ER-α36 expression and tamoxifen resistance was analyzed and confirmed in 709 breast cancer patients with a median follow-up of 7.9 years. Lignans, the primary active components found in flaxseed, have an antitumor effect, particularly in breast cancer. We have isolated a series of novel lignan compounds, named Vitexins, from the seed of the Chinese herb Vitex Negundo. Studies demonstrated that a mixture of Vitexin lignans EVn-50 has superior and broad antitumor activity on breast and many other different cancer xenograft models. Purified natural Vitexin compound VB6 reverses tamoxifen resistance, and inhibits tamoxifen-stimulated and ER-α36-mediated MIES and mTOR activation. We will test two hypotheses: 1) SNCG and ER-α36 are two new molecular targets for endocrine resistance in breast cancer, in which SNCG chaperones and stimulates ER-α36-mediated MIES, and thus induces resistance to endocrine therapy (such as tamoxifen); 2) VB6 reverses tamoxifen resistance by inhibiting ER-α36 mediated tamoxifen agonist action, which might be manifested at two levels: a) inhibiting tamoxifen binding to ER-α36; and/or b) inhibiting ER-α36 signaling. We will study: 1) the mechanism(s) by which SNCG stimulates membrane-initiated MIES; 2) if ER-α36 mediates tamoxifen agonist activity by stimulating MIES in breast cancer cells; and 3) if VB6 reverses tamoxifen resistance by antagonizing ER-α36. The study will provide important and novel information on SNCG, ER-α36 and tamoxifen resistance, which will help developing VB6 as potential cancer intervention drug, particularly for the treatment of hormone refractory breast cancer.

内分泌治疗(ET)是雌激素受体α(ERα)-阳性乳腺癌患者综合治疗的重要部分；但因耐药而限制其临床应用。突触核蛋白γ(SNCG)是一个新的乳腺癌预后指标，调控包括ERα在内的多种信号传导。ER-α36是ERα的新亚型，能介导非基因组细胞膜受体启动雌激素信号传导(MIES)。木脂素(一种植物多聚酚类化合物)具有癌症预防和治疗作用。从植物药黄荆子中，我们发现一系列新的木脂素Vitexins，其中VB6可逆转ET药物他莫昔芬(TAM)耐药，抑制TAM的诱导和ER-α36介导的MIES。本课题将验证两种假说：(1)SNCG和ER-α36是ET耐药的两个新的分子靶点，SNCG通过分子伴侣作用保护和激活ER-α36；而ER-α36通过MIES引起ET耐药；（2）VB6具有ER-α36拮抗剂功能而逆转ET耐药。本研究将对ET的耐药机制提供全新的理论基础。同时也为VB6作为对激素治疗耐药的乳腺癌提供依据。

内分泌治疗(ET)是雌激素受体α(ERα)-阳性乳腺癌患者综合治疗的重要部分；但因耐药而限制其临床应用。突触核蛋白γ(SNCG)是一个新的乳腺癌预后指标，调控包括ERα在内的多种信号传导。ER-α36是ERα的新亚型，能介导非基因组细胞膜受体启动雌激素信号传导(MIES)。木脂素(一种植物多聚酚类化合物)具有癌症预防和治疗作用。从植物药黄荆子中，我们发现一系列新的木脂素Vitexins，其中VB6可逆转ET药物他莫昔芬(TAM)耐药，抑制TAM的诱导和ER-α36介导的MIES。本课题将验证两种假说：(1)SNCG和ER-α36是ET耐药的两个新的分子靶点，SNCG通过分子伴侣作用保护和激活ER-α36；而ER-α36通过MIES引起ET耐药；（2）VB6具有ER-α36拮抗剂功能而逆转ET耐药。本研究将对ET的耐药机制提供全新的理论基础。同时也为VB6作为对激素治疗耐药的乳腺癌提供依据。