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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Microenvironment Study Section (TME)
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Mohla, Suresh
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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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
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
Rehman, Sumaiyah K; Li, Shau-Hsuan; Wyszomierski, Shannon L et al. (2014) 14-3-3ýý orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation. Cancer Res 74:363-73
Zhang, Siyuan; Huang, Wen-Chien; Zhang, Lin et al. (2013) SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases. Cancer Res 73:5764-74
Neal, C L; Xu, J; Li, P et al. (2012) Overexpression of 14-3-3? in cancer cells activates PI3K via binding the p85 regulatory subunit. Oncogene 31:897-906
Zhang, Siyuan; Huang, Wen-Chien; Li, Ping et al. (2011) Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 17:461-9
Esteva, Francisco J; Guo, Hua; Zhang, Siyuan et al. (2010) PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 177:1647-56
Neal, Christopher L; Yu, Dihua (2010) 14-3-3? as a prognostic marker and therapeutic target for cancer. Expert Opin Ther Targets 14:1343-54
Lu, Jing; Guo, Hua; Treekitkarnmongkol, Warapen et al. (2009) 14-3-3zeta Cooperates with ErbB2 to promote ductal carcinoma in situ progression to invasive breast cancer by inducing epithelial-mesenchymal transition. Cancer Cell 16:195-207
Li, Shau-Hsuan; Hawthorne, Valerie S; Neal, Christopher L et al. (2009) Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through nuclear factor-kappaB activation. Cancer Res 69:9163-8

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