MicroRNAs (miRNAs) appear to play a role in mediating interactions between cancer cells and their hosting niche during cancer progression and metastasis. Our preliminary studies indicate that miR-105, whose levels in the circulation are associated with metastatic progression in early-stage breast cancer (BC) patients, is characteristically expressed and secreted by metastatic BC (MBC) cells. MiR-105 downregulates the tight junction protein ZO-1, for which reduced expression is associated with metastasis in BC patients. MiR-105 potently induces migration and proliferation in MBC cells, and can be transferred via MBC-secreted exosomes to normal epithelial and endothelial cells in the cancer niche, where it alters ZO-1 expression and the barrier function of these niche cells. In a mouse model established in our lab, MBC-secreted exosomes and miRNAs can be internalized by cells in various tissues, and can facilitate metastasis development. The goals of this study are to dissect the dual roles of miR-105 in regulating the metastatic potential of cancer cells and in destroying the epithelial and endothelial "barriers" in the cancer niche, and t explore novel therapeutic strategies that target miR-105-mediated pro-metastatic functions.
In Aim 1, the effects of miR-105 on cancer cell adhesion, migration, invasion, proliferation and anchorage-independent growth, as well as the role of ZO-1 in mediating these effects, will be investigated. Additional miR-105-regulated genes will be identified and their role in mediating miR-105's effects will be determined.
In Aim 2, the effects of cancer-secreted, exosome-transferred miR-105 on normal epithelial and endothelial niche cells will be determined, focusing on their "barrier" functions to restrict cancer cell invasion and metastasis. The magnitude and kinetics of miR-105-mediated barrier-destroying effects will be determined by co-culturing the epithelial and endothelial niche cells with MBC cells that secrete miR-105.
In Aim 3, the in vivo effects of miR-105 on niche adaptation and BC metastasis will be determined using mouse xenograft models of BC. The anti-metastatic effect of miR- 105 intervention will be evaluated. These in-depth functional studies of cancer-secreted miRNAs that contribute to the co-evolution of the tumor-hosting environment will provide novel insights into the dynamic communication between cancer and host during disease progression. This study will also provide proof-of- principle for targeting cancer-secreted miRNAs as a novel approach to block the cancer-directed, pro-metastatic remodeling of the niche at early cancer stages for the prevention of metastasis. Our long-term objectives are to validate the miR-105 pathway in primary BC and establish standard approaches to identify patients suitable for therapies that target miR-105, to understand the global effects of cancer-secreted miRNAs, and to elucidate cancer-secreted, circulating miRNAs (e.g., miR-105) in BC patients as blood-borne markers for early diagnosis or prediction of metastasis.

Public Health Relevance

Metastasis, the leading cause of mortality in cancer patients, is a multi-event process that involves interplay between cancer cells and the cancer-hosting niche. Our previous studies suggest that miR-105, a microRNA characteristically produced and secreted by metastatic breast cancer cells, can be transferred from cancer to the niche, and disrupt the anti-cancer barriers in the normal niche to promote metastasis. In the proposed study, we will dissect the dual role of miR-105 in regulating the potential of cancer cells to spread and in adapting the cancer niche, and will explore novel therapeutic strategies that target miR-105 to block this unique communication between cancer and host, and ultimately, to prevent metastasis.

National Institute of Health (NIH)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Jhappan, Chamelli
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City of Hope/Beckman Research Institute
United States
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Zhou, Weiying; Fong, Miranda Y; Min, Yongfen et al. (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25:501-15
Liu, Liang; Zhou, Weiying; Cheng, Chun-Ting et al. (2014) TGF? induces "BRCAness" and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes. Mol Cancer Res 12:1597-609
Chow, Amy; Zhou, Weiying; Liu, Liang et al. (2014) Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-?B. Sci Rep 4:5750