雄激素受体的作用机制及其作为治疗HER2阳性乳腺癌新方法的临床前期研究

Trastuzumab resistance is a major clinical challenge in treating HER2 positive breast cancer patients. Recent published studies indicate that androgen receptor (AR) is widely expressed in HER2+ breast cancer. However, it is still unclear whether AR plays any role in HER2+ breast cancer. According to our key unpublished results, we hypothesize that AR and HER2 interact with each other to promote the growth of HER2+ breast cancer cells. One prediction from this hypothesis is that the new generation of AR inhibitor enzalutamide should inhibit the growth of HER2+ breast cancer cells. There are three aims in our proposal: 1) To examine the novel mechanism by which AR acts to promote the growth of HER2+ breast cancer cells. 2) To examine the efficacy and the mechanism of action of AR inhibitor enzalutamide in inhibiting the growth of HER2+ breast cancer in xenograft model. 3) To examine whether AR inhibitor enzalutamide can overcome trastuzumab resistance of HER2+ breast cancer in xenograft model. The results of our study will likely uncover novel mechanism of AR in driving the growth of HER2+ breast cancer. In addition, our study will provide critical preclinical data to support a new therapeutic strategy for HER2+breast cancer in which AR targeting helps increase response to trastuzumab treatment and overcome trastuzumab resistance.

HER2阳性（+）乳腺癌对HER2靶向治疗药物曲妥珠单抗的耐药性一直是临床治疗的难题。最近报道雄激素受体（简写，AR）在HER2+乳腺癌中表达很普遍，但AR在HER2+乳腺癌中的作用还不清楚。根据我们的预实验结果，我们假设HER2和AR 相互作用促进了HER2+乳腺肿瘤细胞的生长。我们预测在异种移植肿瘤模型中新一代AR抑制剂Enzalutamide（恩杂鲁胺）应能抑制HER2+乳腺肿瘤细胞生长。本项目有3个目标：1）探讨AR促进HER2+乳腺肿瘤细胞生长的机理；2）检测恩杂鲁胺在异种移植HER2+乳腺肿瘤模型中的功效；3）检测恩杂鲁胺能否在异种移植肿瘤模型中克服曲妥珠单抗耐药性。本研究将揭示AR促进HER2+乳腺细胞生长的分子机理，并为以AR为靶点来提高曲妥珠单抗的敏感性和克服曲妥珠单抗的耐药性提供重要的临床前研究证据。

HER2阳性乳腺癌（+）约占所有乳腺癌的25％，并且具有更差的预后。曲妥珠单抗是首个有效治疗HER2+乳腺癌的靶向HER2的药物，但是先天性和获得性曲妥珠单抗耐药一直临床上治疗HER2+乳腺癌病人的难题。最近报道雄激素受体(AR)在HER2+乳腺癌中表达很普遍，但AR在HER2+乳腺癌 中的作用还不清楚。本项目主要研究包括：1)在体外细胞株水平上探讨了AR促进HER2+乳腺肿瘤细胞生长的分子机理;2)检测新一代AR抑制剂恩杂鲁胺在异种移植HER2+乳腺肿瘤模型中的功效;3)检测恩杂鲁胺能否在异种移植肿瘤模型中克服曲妥珠单抗耐药性。研究发现，在HER2+乳腺癌细胞中，AR与蛋白酪氨酸激酶Src和HER2的相互作用来激活Src，从而增强HER2的活性以及HER2下游通路Akt和Erk的激活，最终促进HER2+乳腺癌细胞的存活和增殖。在异种移植模型中，恩杂鲁胺通过促进细胞凋亡和降低细胞增殖来抑制HER2+乳腺肿瘤的生长。次外，恩杂鲁胺与曲妥珠单抗联用可以有效的抑制异种移植肿瘤模型中妥珠单抗耐药的HER2+乳腺肿瘤的生长。本项目揭示了雄激素受体促进HER2+乳腺细胞生长的新颖分子机制，并为以AR为治疗靶点来提高曲妥珠单抗的敏感性和克服曲妥珠单抗的耐药性提供重要的临床前研究证据。我们的研究表明，用于治疗前列腺癌的药物恩杂鲁胺也可以用来治疗对曲妥珠单抗不敏感的HER2+/AR+乳腺癌病人。