Mucin 1 (MUC1) is aberrantly overexpressed in ~90% of human breast cancers and, as such, has been regarded as a highly attractive target for the development of new anti-cancer agents. However, progress in the identification of drugs that block MUC1 had been previously limited by a lack of understanding as to how MUC1 contributes to malignant progression. In this regard, MUC1 consists of two subunits, and early research focused on the shed extracellular mucin subunit (MUC1-N). Work supported by this grant has now demonstrated that the transmembrane MUC1-C subunit functions as an oncoprotein and is a druggable target for the development of novel therapeutic agents. MUC1-C represents a potentially selective target in that the Muc1 knock-out mouse is viable and has no evident phenotype. In addition, the MUC1-C subunit is normally positioned in an inactive state at the apical borders of mammary epithelial cells. With transformation and loss of polarity, MUC1-C associates with receptor tyrosine kinases at the breast cancer cell membrane and localizes to the cytoplasm, nucleus and mitochondria. The potential selectivity of MUC1-C as a target is further supported by the demonstration that MUC1-C inhibitors are highly effective in the treatment of human breast tumor xenografts in mice without normal tissue toxicity. The overall objective of the proposed work is to improve scientific knowledge, therapeutic capability and clinical practice by targeting MUC1-C with novel approaches that block its oncogenic function. Our hypothesis is that the MUC1-C oncoprotein is a druggable target that can be inhibited at the cell membrane and within the breast cancer cell. The proposed work will address this hypothesis by providing (i) new insights into how inhibition of MUC1-C function blocks growth and survival of breast cancer cells, and (ii) new therapeutic agents that will be evaluated preclinically for potential development in the clinic for the treatment of breast cancer.
The Specific Aims are: (1) To assess potential therapeutic approaches that target the MUC1-C subunit extracellular domain at the breast cancer cell surface;(2) To evaluate the development of orally bioavailable MUC1-C peptide inhibitors that block its function in the cytoplasm;(3) To define the activity of peptide and small molecule inhibitors of MUC1-C function in the nucleus and mitochondria;and (4) To identify effective combinations of MUC1-C inhibitors with targeted anti-cancer agents for breast cancer treatment.

Public Health Relevance

Breast cancer is one of the leading causes of death for women. The MUC1 oncoprotein is expressed at high levels in approximately 90% of human breast tumors and contributes to carcinogenesis. Our proposed research focuses on the development of new therapeutic agents that target MUC1 for the treatment of patients with breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA097098-10A1
Application #
8371090
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Alley, Michael C
Project Start
2002-07-01
Project End
2017-04-30
Budget Start
2012-07-11
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$363,125
Indirect Cost
$155,625
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Alam, Maroof; Ahmad, Rehan; Rajabi, Hasan et al. (2015) MUC1-C Induces the LIN28B?LET-7?HMGA2 Axis to Regulate Self-Renewal in NSCLC. Mol Cancer Res 13:449-60
Alam, Maroof; Rajabi, Hasan; Ahmad, Rehan et al. (2014) Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells. Oncotarget 5:2622-34
Kharbanda, Akriti; Rajabi, Hasan; Jin, Caining et al. (2014) MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells. Oncotarget 5:8893-905
Kumar, Manoj; Gupta, Dikshi; Singh, Gurpal et al. (2014) Novel polymeric nanoparticles for intracellular delivery of peptide Cargos: antitumor efficacy of the BCL-2 conversion peptide NuBCP-9. Cancer Res 74:3271-81
Rajabi, H; Alam, M; Takahashi, H et al. (2014) MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition. Oncogene 33:1680-9
Kharbanda, Akriti; Rajabi, Hasan; Jin, Caining et al. (2014) Targeting the oncogenic MUC1-C protein inhibits mutant EGFR-mediated signaling and survival in non-small cell lung cancer cells. Clin Cancer Res 20:5423-34
Uchida, Yasumitsu; Raina, Deepak; Kharbanda, Surender et al. (2013) Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells. Cancer Biol Ther 14:127-34
Kharbanda, Akriti; Rajabi, Hasan; Jin, Caining et al. (2013) Oncogenic MUC1-C promotes tamoxifen resistance in human breast cancer. Mol Cancer Res 11:714-23
Alam, Maroof; Ahmad, Rehan; Rajabi, Hasan et al. (2013) MUC1-C oncoprotein activates ERKýýýC/EBP* signaling and induction of aldehyde dehydrogenase 1A1 in breast cancer cells. J Biol Chem 288:30892-903
Raina, Deepak; Ahmad, Rehan; Rajabi, Hasan et al. (2012) Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. Int J Oncol 40:1643-9

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