Roles of microRNA-140 in stem cell-associated early stage breast cancer

Abstract

An increasing body of evidence supports a stepwise model for progression of breast cancer from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Due to the high level of DCIS heterogeneity, we cannot currently predict which patients are at highest risk for disease recurrence or progression. The mechanisms of progression are still largely unknown, however cancer stem cell populations in DCIS lesions may serve as malignant precursor cells intimately involved in progression. While genetic and epigenetic alterations found in DCIS are often shared by IDC, mRNA and miRNA expression profiles are significantly altered. Therapeutic targeting of cancer stem cell pathways and differentially expressed miRNA could have significant clinical benefit. As tumor grade increases, miRNA-140 is progressively downregulated. miR-140 plays an important tumor suppressive role in the Wnt, SOX2 and SOX9 stem cell regulator pathways. Downregulation of miR-140 removes inhibition of these pathways, leading to higher cancer stem cell populations and breast cancer progression. miR-140 downregulation is mediated through both an estrogen response element in the miR-140 promoter region and differential methylation of CpG islands. These mechanisms are novel targets for epigenetic therapy to activate tumor suppressor signaling via miR-140. Additionally, we briefly explored the emerging role of exosomes in mediating intercellular miR-140 signaling. The purpose of this review is to examine the cancer stem cell signaling pathways involved in breast cancer progression, and the role of dysregulation of miR-140 in regulating DCIS to IDC transition.

Keywords: Breast cancer, Ductal carcinoma in situ, Invasive ductal carcinoma, Cancer stem cells, MicroRNA-140

Core tip: MiR-140 is an important tumor suppressor. By inhibiting stem cell growth through interaction with the Wnt, SOX2 and SOX9 pathways, breast cancer initiation, progression and growth are reduced. miR-140 is progressively downregulated as breast cancer grade decreases, through both estrogen binding and differential methylation in the miR-140 promoter region. By targeting these mechanisms using epigenetic therapy miR-140 tumor suppressor signaling can be reactivated.