Stromal activation in the progression of high ErbB2/1433zeta DCIS to IBC

描述（由申请人提供）：研究从非浸润性导管原位癌（DCIS）到危及生命的浸润性乳腺癌（IBC）的转变被美国国家科学院医学研究所列为100项研究重点的前四分之一。 该提案探讨了创新方法，以更好地了解早期DCIS如何发展为IBC。 我们最近发现，当DCIS病变高度表达两种基因（ErbB 2和14-3-3？）时，它们很容易发展为IBC，我们已经确定了肿瘤细胞中的关键分子改变，这些改变有助于发展为IBC，并增加侵袭。 然而，乳腺癌的进展并不是肿瘤细胞的“单独”表现。 它是肿瘤细胞及其周围微环境基质成分之间复杂相互作用的结果。 事实上，我们的初步数据表明，ErbB 2和14-3-3？共过表达的乳腺肿瘤细胞在肿瘤进展过程中动态地与基质相互作用并激活基质。 因此，我们推测ErbB 2/14-3-3？共过表达的乳腺癌细胞改变了它们的基质成分，并将正常基质（肿瘤抑制性）转化为活化基质（肿瘤促进性），这无疑提供了一个允许的微环境，以促进从DCIS进展为IBC。 在这里，我们提出了三个具体的目的，以探讨间质激活的作用，在ErbB 2/1433？使用乳腺特异性14-3- 3？共过表达DCIS至IBC。双转基因小鼠模型、人MEC和患者的乳腺肿瘤样品。 我们将1）确定ErbB 2和14-3-3？探讨ErbB 2和14-3-3在乳腺肿瘤间质中的共过表达，以及活化的间质对肿瘤进展和转移的作用;共过表达乳腺肿瘤诱导间质活化; 3）检查ErbB 2/1433？+中间质活化的临床相关性患者的DCIS及其与进展为IBC和转移性乳腺癌的相关性。 值得注意的是，这些建议的研究ErbB 2/14-3-3之间的相互作用的功能影响和机制？共同过表达乳腺肿瘤细胞及其动态基质微环境将为DCIS如何进展为IBC带来令人兴奋的新生物学见解，并可能影响患者的临床管理。 这可能为开发未来策略开辟新的途径，通过重建抑制性微环境来逆转活化基质的肿瘤增强效应，以有效预防或逆转DCIS向IBC的致命转变。

DESCRIPTION (provided by applicant): Studying the transition from non-invasive ductal carcinoma in situ (DCIS) to life-threatening invasive breast cancer (IBC) is listed in the top quartile of the 100 research priorities by the Institute of Medicine of the National Academies. This proposal explores innovative ways to better understand how early stage DCIS progresses to IBC. We recently found that when a DCIS lesion highly expresses two genes (ErbB2 and 14-3-3?), they readily progress to IBC, and we have identified key molecular alterations in tumor cells contributing to this progression to IBC with increased invasion. However, breast cancer progression is not a "solo" performance of tumor cells. It evolves as the result of sophisticated interaction between tumor cells and their surrounding microenvironment stromal components. Indeed, our preliminary data indicate that ErbB2 and 14-3-3? co-overexpressing mammary tumor cells dynamically interact with and activate stroma during tumor progression. Therefore, we hypothesize that ErbB2/14-3-3? co-overexpressing breast cancer cells alter their stromal components and convert normal stroma (tumor suppressive) to activated stroma (tumor- promoting), which reciprocally provide a permissive microenvironment to promote progression from DCIS to IBC. Here, we propose three Specific Aims to explore the roles of stroma activation in the progression of ErbB2/1433? co-overexpressing DCIS to IBC using mammary gland-specific 14-3- 3?.neu bitransgenic mouse models, human MECs, and patients' breast tumor samples. We will 1) Determine the effects of ErbB2 and 14-3-3? co-overexpression in mammary tumors on their stroma, and the contribution of activated stroma to tumor progression and metastasis; 2) Investigate the molecular mechanisms by which ErbB2 and 14-3-3? co-overexpressing mammary tumors induce stromal activation; 3) Examine the clinical relevance of stromal activation in ErbB2/1433?+++ DCIS from patients and its association with progression to IBC and metastatic breast cancer. Significantly, these proposed studies on the functional impact and mechanisms of the reciprocal interactions between ErbB2/14-3-3? co-overexpressing breast tumor cells and their dynamic stromal microenvironment will bring exciting new biological insights on how DCIS progressing to IBC and may impact on the clinical management of patients. This could open a new venue for development of future strategies to reverse the tumor-enhancing effects of the activated stroma by re-establishing a suppressive microenvironment to effectively prevent or reverse the deadly transition of DCIS to IBC.