Patients with ductal carcinoma in situ (DCIS) have significant risks of developing recurrence or invasive breast cancer even after they receive breast surgery. Thus, women stand to benefit from chemoprevention strategies that reduce the incidence of DCIS recurrence. However, the molecular mechanisms that underlie DCIS development remain unclear and so it is important to identify pathways that could be targeted for prevention. Our preliminary studies showed that loss of microRNA-140 (miR-140) expression is associated with the development of DCIS and that sulforaphane (a key bioactive ingredient of cruciferous vegetables) can restore miR-140 expression in primary DCIS cells. We further observed that reduced miR-140 expression is associated with increased expression of the SIRT1 histone deacetylase that is associated with enhanced cancer stem cell survival. Finally, miR-140 knockout mice spontaneously developed DCIS at 11 months of age. Our preliminary data suggest that miR-140 and SIRT1 have roles in DCIS development. Based on these results, we hypothesize that miR-140 loss leads to increased SIRT1 expression which drives DCIS development and increased accumulation of breast cancer stem cells. We further propose that sulforaphane treatment can restore miR-140 level which then targets and suppresses SIRT1 level to prevent DCIS development.
Specific Aim 1 will define the mechanism of miR-140 inactivation in DCIS transformation.
Specific Aim 2 is designed to determine the impact of miR-140 on cancer stem cell survival in DCIS transformation.
Specific Aim 3 is designed to characterize the role of miR-140 in sulforaphane chemoprevention of DCIS in vivo. We believe that these studies are innovative and "high impact" because findings from our studies will identify a new mechanism of DCIS development and a new route of sulforaphane-dependent breast cancer prevention. We have developed all of the cell-based and animal models necessary to complete these studies.

Public Health Relevance

Our studies strongly suggest that sulforaphane may be an important chemopreventive agent to suppress DCIS by correcting the epigenetic regulation to restore miR-140 expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA163820-01A1
Application #
8304781
Study Section
Special Emphasis Panel (ZRG1-OTC-B (02))
Program Officer
Ross, Sharon A
Project Start
2012-06-01
Project End
2017-03-31
Budget Start
2012-06-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$318,513
Indirect Cost
$111,013
Name
University of Maryland Baltimore
Department
Biochemistry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Li, Qinglin; Eades, Gabriel; Yao, Yuan et al. (2014) Characterization of a stem-like subpopulation in basal-like ductal carcinoma in situ (DCIS) lesions. J Biol Chem 289:1303-12
Li, Q; Yao, Y; Eades, G et al. (2014) Downregulation of miR-140 promotes cancer stem cell formation in basal-like early stage breast cancer. Oncogene 33:2589-600
Li, Qinglin; Xia, Jixiang; Yao, Yuan et al. (2013) Sulforaphane inhibits mammary adipogenesis by targeting adipose mesenchymal stem cells. Breast Cancer Res Treat 141:317-24