The major goal of
breast cancer prevention is to reduce the incidence of
ductal carcinoma in situ (
DCIS), an early stage of
breast cancer. However, the biology behind
DCIS formation is not well understood. It is suspected that cancer stem cells (CSCs) are already programmed in pre-malignant
DCIS lesions and that these tumor-initiating cells may determine the phenotype of
DCIS.
MicroRNA (
miRNA) profiling of paired
DCIS tumors revealed that loss of miR-140 is a hallmark of
DCIS lesions. Previously, we have found that miR-140 regulates CSCs in
luminal subtype invasive
ductal carcinoma. Here, we find that miR-140 has a critical role in regulating stem cell signaling in normal breast epithelium and in
DCIS.
miRNA profiling of normal mammary stem cells and
cancer stem-like cells from
DCIS tumors revealed that miR-140 is significantly downregulated in
cancer stem-like cells compared with normal stem cells, linking miR-140 and dysregulated stem cell circuitry. Furthermore, we found that SOX9 and ALDH1, the most significantly activated stem-cell factors in
DCIS stem-like cells, are direct targets of miR-140. Currently, targeted
therapies (
tamoxifen) are only able to reduce
DCIS risk in patients with
estrogen receptor α (ERα)-positive disease. We examined a model of ERα-negative/basal-like
DCIS and found that restoration of miR-140 via a genetic approach or with the dietary compound
sulforaphane decreased SOX9 and ALDH1, and reduced
tumor growth in vivo. These results support that a miR-140/ALDH1/SOX9 axis is critical to basal CSC self-renewal and
tumor formation in vivo, suggesting that the miR-140 pathway may be a promising target for preventative strategies in patients with basal-like
DCIS.