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

描述(申请人提供)：从非浸润性导管原位癌(DCIS)到威胁生命的浸润性乳腺癌(IBC)的研究被列为美国国家科学院医学研究所100项研究重点的前四分之一。这项建议探索了创新的方法，以更好地了解早期DCIS是如何进展到IBC的。我们最近发现，当DCIS病变高表达两个基因(ErbB2和14-3-3？)时，它们很容易进展为IBC，我们发现肿瘤细胞中的关键分子变化有助于这种进展为IBC并增加侵袭性。然而，乳腺癌的进展并不是肿瘤细胞的“单独”表现。它是肿瘤细胞与其周围微环境间质成分复杂相互作用的结果。事实上，我们的初步数据表明，ErbB2和14-3-3？共表达的乳腺肿瘤细胞在肿瘤进展过程中动态地与间质相互作用并激活。因此，我们假设ErbB2/14-3-3？共表达的乳腺癌细胞改变它们的间质成分，将正常的间质(抑制肿瘤)转化为激活的间质(促进肿瘤)，从而相互提供一个允许的微环境，促进从DCIS到IBC的进展。在这里，我们提出了三个具体的目标，以探索基质激活在ErbB2/1433？使用乳腺特异的14-3-3？neu双转基因小鼠模型、人微血管内皮细胞和患者的乳腺肿瘤样本将DCIS共表达到IBC。我们将1)确定ErbB2和14-3-3的作用。2)探讨ErbB2和14-3-3？3)检测患者ErbB2/1433？+DCIS中间质激活的临床相关性及其与IBC进展和转移性乳腺癌的关系。值得注意的是，这些关于ErbB2/14-3-3？共表达的乳腺肿瘤细胞及其动态的间质微环境将为DCIS如何进展为IBC带来令人兴奋的新的生物学见解，并可能影响患者的临床治疗。这可能为制定未来的策略开辟新的场所，通过重新建立抑制微环境来逆转激活的间质的肿瘤增强效应，从而有效地防止或逆转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.