title: Targeted imaging of breast tumor progression and therapeutic response in a human uMUC-1 expressing transgenic mouse model.
abstract: The ability to monitor breast cancer initiation and progression on the molecular level would provide an effective tool for early diagnosis and therapy. In the present study, we focused on the underglycosylated MUC-1 tumor antigen (uMUC-1), which is directly linked to tumor progression from pre-malignancy to advanced malignancy in breast cancer and has been identified as the independent predictor of local recurrence and tumor response to chemotherapy. We investigated whether changes in uMUC-1 expression during tumor development and therapeutic intervention could be monitored non-invasively using molecular imaging approach with the uMUC-1-specific contrast agent (MN-EPPT) detectable by magnetic resonance and fluorescence optical imaging. This was done in mice that express human uMUC-1 tumor antigen (MMT mice) and develop spontaneous mammary carcinoma in a stage-wise fashion. After the injection of MN-EPPT there was a significant reduction in average T2 relaxation times of the mammary fat pad between pre-malignancy and cancer. In addition, T2 relaxation times were already altered at pre-malignant state in these mice compared to non-tumor bearing mice. This indicated that targeting uMUC-1 could be useful for detecting pre-malignant transformation in the mammary fat pad. We also probed changes in uMUC-1 expression with MN-EPPT during therapy with doxorubicin (Dox). We observed that tumor delta-T2s were significantly reduced by treatment with Dox indicating lower accumulation of MN-EPPT. This correlated with a lower level of MUC-1 expression in the Dox-treated tumors, as confirmed by immunoblotting. Our study could provide a very sensitive molecular imaging approach for monitoring tumor progression and therapeutic response.
authors.affiliation: Molecular Imaging Laboratory, MGH/HST Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Ghosh
authors.forename: Masashi
authors.initials: M
authors.lastname: Uchida
authors.forename: Byunghee
authors.initials: B
authors.lastname: Yoo
authors.forename: Alana W
authors.initials: AW
authors.lastname: Ross
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
authors.forename: Jianlin
authors.initials: J
authors.lastname: Gong
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
authors.forename: Zdravka
authors.initials: Z
authors.lastname: Medarova
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057054:Molecular Imaging; D018396:Mucin-1 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C060192:MUC1 protein, human; D018396:Mucin-1; D004317:Doxorubicin