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项研究重点中的前四分之一。该提案探索了创新的方法，以更好地了解早期DCIS如何发展到IBC。我们最近发现，当DCIS病变高度表达两个基因（ErbB2和14-3-3?）时，它们很容易发展为IBC，并且我们已经确定了肿瘤细胞中促进IBC进展的关键分子改变，并增加了侵袭。然而，乳腺癌的进展并不是肿瘤细胞的“单独”表现。它是肿瘤细胞与其周围微环境基质组分之间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？共同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，我们假设ErbB2/14-3-3？共过表达的乳腺癌细胞改变其基质成分，将正常基质（肿瘤抑制）转化为活化基质（肿瘤促进），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，我们提出了三个特定的目的来探索基质激活在ErbB2/1433？使用乳腺特异性14-3-3 -3 ?向IBC共过表达DCIS。新型双转基因小鼠模型、人mec和患者乳腺肿瘤样本。我们将1)确定ErbB2和14-3-3？乳腺肿瘤间质共过表达及活化间质对肿瘤进展转移的影响2)探讨ErbB2与14-3-3？共过表达乳腺肿瘤诱导基质活化；3)检查基质激活在ErbB2/1433中的临床意义？患者DCIS及其与IBC和转移性乳腺癌进展的关系。值得注意的是，这些关于ErbB2/14-3-3？共同过表达乳腺肿瘤细胞及其动态基质微环境将为DCIS如何发展为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。这可能为未来策略的发展开辟了一个新的领域，通过重建一个抑制性微环境来逆转激活基质的肿瘤增强效应，从而有效地预防或逆转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. PUBLIC HEALTH RELEVANCE: Breast cancer affects one out of eight women in this country and the transition from non-invasive ductal carcinoma in situ (DCIS) to life-threatening invasive breast cancer (IBC) is the key step in breast cancer progression that ultimately leads to patient death. Our proposed investigations will shed new light on the mechanism of the deadly transition of ErbB2/1433? co-overexpressing DCIS to IBC by exploring the roles of ErbB2/1433?-mediated alterations of both tumor cells and their surrounding stroma microenvironment. The timely information will lead to improved patient care by opening a new venue for development of future strategies to reverse the tumor-enhancing effects of the activated stroma via re-establishing a suppressive microenvironment to effectively prevent or reverse DCIS progression to IBC.