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.
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.
|Zhang, Chenyu; Yu, Dihua (2016) Advances in decoding breast cancer brain metastasis. Cancer Metastasis Rev :|
|Chang, Chia-Chi; Zhang, Chenyu; Zhang, Qingling et al. (2016) Upregulation of lactate dehydrogenase a by 14-3-3Î¶ leads to increased glycolysis critical for breast cancer initiation and progression. Oncotarget 7:35270-83|
|Acharya, Sunil; Xu, Jia; Wang, Xiao et al. (2016) Downregulation of GLUT4 contributes to effective intervention of estrogen receptor-negative/HER2-overexpressing early stage breast disease progression by lapatinib. Am J Cancer Res 6:981-95|
|Zhang, Lin; Zhang, Siyuan; Yao, Jun et al. (2015) Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527:100-4|
|Brady, Samuel W; Zhang, Jian; Tsai, Ming-Horng et al. (2015) PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTOR and Hsp90 inhibition. Cancer Biol Ther 16:402-11|
|Xu, Jia; Acharya, Sunil; Sahin, Ozgur et al. (2015) 14-3-3Î¶ turns TGF-Î²'s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2. Cancer Cell 27:177-92|
|Jain, Shalini; Wang, Xiao; Chang, Chia-Chi et al. (2015) Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer. Cancer Res 75:4863-75|
|Sahin, Ozgur; Wang, Qingfei; Brady, Samuel W et al. (2014) Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors. Cell Res 24:542-59|
|Rehman, Sumaiyah K; Li, Shau-Hsuan; Wyszomierski, Shannon L et al. (2014) 14-3-3Ã½Ã½ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation. Cancer Res 74:363-73|
|Brady, Samuel W; Zhang, Jian; Seok, Daniel et al. (2014) Enhanced PI3K p110* signaling confers acquired lapatinib resistance that can be effectively reversed by a p110*-selective PI3K inhibitor. Mol Cancer Ther 13:60-70|
Showing the most recent 10 out of 21 publications