Transcriptomic analysis of mammary tumors from MMTV-ErbB2 transgenic mice. Mus musculus

The tyrosine kinase ErbB2 positive breast tumors have more aggressive tumor growth, poorer clinical outcome, and more resistance to radiotherapy, chemotherapy and hormone therapy. A humanized anti-ErbB2 monoclonal antibody Herceptin and a small molecules inhibitor Lapatinib were developed and approved by FDA to treat patients with ErbB2 amplification and overexpression. Unfortunately, most ErbB2+ breast cancers do not respond to Herceptin and Lapatinib, and the majority of responders become resistant within 12 months of initial therapy (defined as secondary drug resistance). Such differences in response to Lapatinib treatment is contributed by substantial heterogeneity within ErbB2+ breast cancers. To address this possibility, we carried out transcriptomic analysis of mammary tumors from genetically diverse MMTV-ErbB2 mice. This will help us to have a better understanding of the heterogeneous response to ErbB2 targeted therapy and permit us to design better and more individualized (personalized) treatment strategies for human ErbB2 positive breast cancer. Overall design: 214 MMTV-ErbB2 mammary tumors and 8 normal mammary glands were analyzed by Affymetrix microarrays.

酪氨酸激酶（tyrosine kinase）ErbB2阳性乳腺癌具有更强的侵袭性生长特性、更差的临床结局，且对放疗、化疗及内分泌治疗的耐药性更强。
人源化抗ErbB2单克隆抗体赫赛汀（Herceptin）与小分子抑制剂拉帕替尼（Lapatinib）已被开发，并获美国食品药品监督管理局（FDA）批准，用于治疗ErbB2扩增与过表达的乳腺癌患者。
遗憾的是，多数ErbB2阳性乳腺癌患者无法从赫赛汀与拉帕替尼的治疗中获益，且大部分初始治疗应答者会在启动治疗后的12个月内出现耐药（定义为继发性耐药）。
这种拉帕替尼治疗响应的差异，源于ErbB2阳性乳腺癌内部显著的肿瘤异质性。
为探究这一潜在机制，我们对遗传背景多样化的MMTV-ErbB2小鼠乳腺肿瘤开展了转录组学分析。
该研究将有助于我们更深入理解ErbB2靶向治疗的异质性响应，并为人类ErbB2阳性乳腺癌设计更优化、更具个体化（个性化）的治疗策略。
整体实验设计：采用Affymetrix基因微阵列芯片（Affymetrix microarrays），对214株MMTV-ErbB2小鼠乳腺肿瘤及8例正常乳腺组织进行了检测分析。