EXPERIMENTAL STUDY ON ACTION MECHANISMS OF RESISTANCE TO HORMONAL THERAPY AND OVERCOMING THIS RESISTANCE IN BREAST CANCER

乳腺癌激素治疗抵抗作用机制及克服这种抵抗的实验研究

• 批准号: 14571166
• 负责人: KUREBAYASHI Junichi
• 金额: $ 1.79万
• 依托单位: KAWASAKI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571166/
• 关键词: Berast cancer; Endocrine resistance; Hypoxia; Estrogen receptor; HER1; Signal transduction inhibitor; Hypoxic cytotoxin; Antiestrogen; p21; Bcl-2; アポトーシス; HER1 シグナル伝達阻害剤

Results of this study project are summarized. 1)We investigated the relationship between the expression levels of HER1,HER2,p53 in primary breast cancer tissues by immunohistochemistry and responses to endocrine therapy in patients with recurrent diseases. HER1-overexpressing breast cancers acquired endocrine-resistance earlier and provided a worse prognosis to the patients. 2)A HER1-tyrosine kinase inhibitor, gefitinib (G), enhanced an antitumor effect of an antiestrogen, fulvestrant (F), in estrogen receptor(ER)-positive human breast cancer cells under estrogen-supplemented conditions. This is because G synergistically increased a protein expression level of a cyclin-dependent kinase inhibitor, p21, and this effect resulted in an additive G1-S cell cycle retardation. Additionally, G induced a decrease in an expression level of an anti-apoptotic protein, Bcl-2, and an increase in an apoptotic fraction in ER-negative and HER1 and/or HER2-overexpressing breast cancer cells. 3)Hypoxic cytotoxins, tirapazamine and TX-402, inhibited a decrease in ER expression in tumors transplanted with human breast cancer cells into nude mice. 4)We investigated changes in expression levels of various genes, which are associated with malignant progression of breast cancer, in breast cancer cells induced by a long-term exposure of hypoxia. An increase in an expression level of HER1 was observed in several breast cancer cell lines. Additionally, an increase in mRNA expression levels of VEGF family members and HIF-1α was observed. These experimental results suggest that an increase, in HER1 expression may play an important role in the development of endocrine-resistance in breast cancer. Furthermore, it is suggested that administration of hypoxic cytotoxins or inhibitors of growth factor signal transduction may delay or overcome endocrine-resistance in breast cancer.

总结了本课题的研究结果。1)通过免疫组化方法研究复发性乳腺癌患者原发性乳腺癌组织中HER1、HER2、p53表达水平与内分泌治疗应答的关系。her1过表达的乳腺癌较早获得内分泌抵抗，预后较差。2) her1 -酪氨酸激酶抑制剂吉非替尼(G)在雌激素受体（ER）阳性的人乳腺癌细胞中增强了抗雌激素氟维司汀(F)的抗肿瘤作用。这是因为G协同增加了周期蛋白依赖性激酶抑制剂p21的蛋白表达水平，这种作用导致了G1-S细胞周期延迟。此外，在er阴性和HER1和/或her2过表达的乳腺癌细胞中，G诱导抗凋亡蛋白Bcl-2表达水平降低，凋亡比例增加。3)低氧细胞毒素替拉帕嗪和TX-402抑制裸鼠人乳腺癌细胞移植肿瘤中ER表达的下降。4)我们研究了长期缺氧诱导的乳腺癌细胞中与乳腺癌恶性进展相关的各种基因表达水平的变化。在几种乳腺癌细胞系中观察到HER1表达水平升高。此外，VEGF家族成员和HIF-1α mRNA表达水平升高。这些实验结果表明，HER1表达的增加可能在乳腺癌内分泌抵抗的发展中起重要作用。此外，研究表明，低氧细胞毒素或生长因子信号转导抑制剂可能延缓或克服乳腺癌的内分泌抵抗。

项目成果

紅林淳一: "癌の抗体療法.腫瘍増殖因子を標的とした抗体療法.HER2."Surgery Frontier. 9(3). 45-49 (2002)

Junichi Kubayashi：“癌症的抗体治疗。针对肿瘤生长因子的抗体治疗。HER2。外科前沿 9(3) (2002)。

紅林淳一: "乳がんに対する内分泌療法の考え方-耐性獲得のメカニズムと対策-"血液・腫瘍科. 45(3). 201-206 (2002)

Junichi Kubayashi：“关于乳腺癌内分泌治疗的思考 - 耐药性获得的机制和对策 -” 血液学和肿瘤学 45（3）（2002）。

Kurebayashi, J.: "Inhibition of HER1 signaling pathway enhances antitumor effect of endocrine therapy in breast cancer."Breast Cancer. 11. 38-41 (2004)

Kurebayashi, J.：“抑制 HER1 信号通路可增强乳腺癌内分泌治疗的抗肿瘤作用。”乳腺癌。

紅林 淳一: "低酸素と悪性形質進展"癌治療と宿主. 15. 239-244 (2003)

Junichi Kubayashi：“缺氧和恶性特征的进展”癌症治疗和宿主。15。239-244（2003）。

Otuski T: "Expression of HER family receptor genes and effects, of anti-HER2-antibody on human myeloma cells."International Journal of Oncology. 23(4). 1135-1141 (2003)

Otuski T：“HER 家族受体基因的表达以及抗 HER2 抗体对人骨髓瘤细胞的影响。”国际肿瘤学杂志。