The long-term goal of this project is to identify a new treatment for patients with triple negative breast cancer who have not responded to, or relapsed while on, traditional chemotherapeutics. Patients with this particular subtype of breast cancer have extremely limited therapeutic options due to the absence of hormone receptors. Thus, determining the molecular mechanisms that drive this cancer and identifying new therapeutic strategies is a high priority. Preliminary data from my lab and others demonstrates that miR-200c suppresses migration, invasion, resistance to microtubule targeting agents and a cancer stem cell phenotype. I have demonstrated that restoring miR-200c to triple negative breast cancer cell lines also suppresses their resistance to anoikis. Anoikis is a form of apoptosis that is initiated when the cells lose their interactions with the extracellular matrix, and it has been suggested as a physiological barrier to metastasis. Resistance to anoikis may allow survival of the carcinoma cells during systemic circulation, when they form emboli in the vasculature or lymphatics but are deprived of matrix adhesion. I have found that miR-200c directly targets a cell surface receptor implicated in anoikis resistance in multiple cancer types, neurotrophic tyrosine receptor kinase B (TrkB). Furthermore, neurotrophin 3 (NTF3), a ligand for TrkB has 2 predicted miR-200c binding sites in the 3'UTR. Taken together, this data leads to my hypothesis that miR-200c enhances anoikis sensitivity in breast cancer cells through targeting of a TrkB/NTF3 signaling pathway. The following specific aims test this hypothesis.
Specific aim 1 : Determine if an autocrine signaling loop in TrkB/NTF3 contributes to the ability of miR- 200c to suppress anoikis resistance in breast cancer cells.
Specific aim 2 : Determine if loss of miR-200c correlates with expression of TrkB and NTF3 in breast cancer patient samples.
Specific aim 3 : Study the ability of miR- 200c to sensitize aggressive breast cancer cells to anoikis in an in vivo model of metastasis. By furthering our understanding of how miR-200c affects anoikis resistance in breast cancer, we move closer to the development of this influential miRNA as a therapeutic option.

Public Health Relevance

Breast cancer is the second most deadly cancer a woman will face in her lifetime, with no real treatment options for patients with triple negative breast cancer who do not respond to, or relapse while on, traditional chemotherapy. We have identified a miRNA, miR-200c, that is able to sensitize cells to an inherent cellular program that drives them to die when they are unattached. By utilizing miR-200c as a non-traditional chemotherapeutic, we hope to prevent metastasis by killing cancer cells before they are able to colonize metastatic sites.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09-D (20))
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Schmidt, Michael K
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University of Colorado Denver
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Cittelly, D M; Finlay-Schultz, J; Howe, E N et al. (2013) Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4. Oncogene 32:2555-64
D'Amato, Nicholas C; Howe, Erin N; Richer, Jennifer K (2013) MicroRNA regulation of epithelial plasticity in cancer. Cancer Lett 341:46-55
Howe, Erin N; Cochrane, Dawn R; Richer, Jennifer K (2012) The miR-200 and miR-221/222 microRNA families: opposing effects on epithelial identity. J Mammary Gland Biol Neoplasia 17:65-77
Howe, Erin N; Cochrane, Dawn R; Cittelly, Diana M et al. (2012) miR-200c targets a NF-ýýB up-regulated TrkB/NTF3 autocrine signaling loop to enhance anoikis sensitivity in triple negative breast cancer. PLoS One 7:e49987