The long-term goal of the proposal is to study the role of microRNAs (miRs) in cellular processes linked to human diseases such as cancer, in development of drug resistance and to identify the miRs that can be used as diagnostic/prognostic markers. Breast cancer is the second leading cause of death in women today and one of the most common cancers among women in North America. Tamoxifen (TAM) is the current standard adjuvant therapy in pre-menopausal women with hormone receptor positive breast cancer. Unfortunately, about 30% of these women have tumors that are primarily resistant (de novo) to TAM or develop resistance upon treatment. Recently, alternative endocrine therapies, such as aromatase inhibitors (AI), are found to be more effective in estrogen receptor positive, post-menopausal women with breast cancer. Identification of patients with de novo TAM resistance may derive better benefit from upfront AI treatment. Several molecular mechanisms that contribute to TAM resistance have been studied but none has led to the development of a gene profile that can consistently identify resistant tumors. Recently much attention has been focused on the analysis of miR expression profile in cancer due to their markedly altered expressions in human cancers some of which play a causal role in tumorigenesis. Our recent study has revealed a unique miR expression profile in TAM resistance breast cancer cell line, where expression of miR-221, miR-222 and miR-181 is significantly upregulated compared to the corresponding TAM sensitive cell line. This observation was also validated in Her2/neu positive primary human breast tumors that respond poorly to endocrine therapy. Our hypothesis is that the altered expression of certain miRs and their target mRNAs contribute to the cellular response to TAM. To explore these possibilities we are proposing the following Specific aims: 1A) Identify the target(s) of miR- 221, miR-222 and miR-181 and the biological pathway(s) involved in breast cancer cell lines. 1B) Investigate whether treatment of TAM resistant and sensitive cells with anti-miRs or miR-mimetics directed against these miRs respectively, reverse the response to the drug. 2) Examine if tumor growth in response to TAM in a mouse model of breast cancer can be modulated by overexpressing or underexpressing miR-221, miR-222 and miR-181 using anti-miRs or miR-mimetics respectively. 3) Compare expression profile of miR-221, miR- 222 and miR-181 in TAM responsive and resistant breast tumors. It is hoped that these identified miRs will serve as prognostic markers and potential therapeutic targets in future. They may also help prevent unwarranted use of aromatase inhibitors and improve appropriate use of TAM. This proposal also fits well with the scope of the NIH-R21 program announcement PA-06-299: """"""""Exploratory studies in cancer detection, diagnosis and prognosis'.

Public Health Relevance

Breast cancer is affecting more and more young women globally. The most economically viable and effective treatment of breast cancer in pre-menopausal women is tamoxifen. Unfortunately about 30% of these women will not benefit from this therapy. We propose to identify the microRNA signature of tamoxifen-resistance tumors in our laboratory. MicroRNAs are small RNA molecules identified in plants, animals and even viruses. These small molecules regulate diverse cellular processes, including cell growth and differentiation. Some microRNAs are so profoundly altered in human cancers they can be used as potential diagnostic and prognostic markers. Studying microRNA signature of tamoxifen resistance breast cancer we will be able to identify those young women who will do poorly on the current standard treatment (tamoxifen), and we can design clinical studies to study alternate therapies in such patients. Alternate therapies for such patients include aromatase inhibitors (AI). Aromatase inhibitors can cause significant bone loss and is also much more expensive. By trying to specifically identify the tumors that may not respond to tamoxifen, we can avoid unwarranted use of AIs. This proposed work will also help us in the future to investigate if we can use novel agents to target these pathways and overcome such resistance. This study will also help us design future clinical trials based on these molecular predictions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Arya, Suresh
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Ohio State University
Schools of Medicine
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Ramaswamy, Bhuvaneswari; Lu, Yuanzhi; Teng, Kun-Yu et al. (2012) Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res 72:5048-59
Lu, Yuanzhi; Roy, Satavisha; Nuovo, Gerard et al. (2011) Anti-microRNA-222 (anti-miR-222) and -181B suppress growth of tamoxifen-resistant xenografts in mouse by targeting TIMP3 protein and modulating mitogenic signal. J Biol Chem 286:42292-302
Majumder, Sarmila; Jacob, Samson T (2011) Emerging role of microRNAs in drug-resistant breast cancer. Gene Expr 15:141-51