Epigenetic Regulation of miRNAs and Breast Cancer Stem Cells.

MicroRNAs have emerged as important targets of chemopreventive strategies in breast cancer. We have found that miRNAs are dysregulated at an early stage in breast cancer, in non-malignant Ductal Carcinoma In Situ. Many dietary chemoprevention agents can act by epigenetically activating miRNA-signaling pathways involved in tumor cell proliferation and invasive progression.

Adipocyte activation of cancer stem cell signaling in breast cancer.

Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment, have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6 (IL-6) have a paracrine effect on breast cancer cells.

Targeting exosomes from preadipocytes inhibits preadipocyte to cancer stem cell signaling in early-stage breast cancer.

The tumor microenvironment plays a critical role in regulating breast tumor progression. Signaling between preadipocytes and breast cancer cells has been found to promote breast tumor formation and metastasis. Exosomes secreted from preadipocytes are important components of the cancer stem cell niche.

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

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.

lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.

Unlabelled: Triple-negative (ER(-), HER2(-), PR(-)) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of microRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 downregulation in TNBC was examined.

NRF2/long noncoding RNA ROR signaling regulates mammary stem cell expansion and protects against estrogen genotoxicity.

Long noncoding RNAs (lncRNAs) have emerged as key regulators of gene expression in embryonic stem cell (ESC) self-renewal and differentiation. In ESCs, lncRNAs are regulated at the genetic level via transcription factor binding to lncRNA gene promoters. Here we demonstrate that the key cytoprotective transcription factor NRF2 controls lncRNA expression in mammary stem cells.

Examining estrogen regulation of cancer stem cells through multicolor lineage tracing.

We have designed a dual-color fluorescent reporter that can track microRNA expression in vitro, which can be used for lineage tracing experiments. We have used this system to track miR-140 promoter activity in breast cancer cells and to follow the impact of estrogen signaling in cancer stem cell subpopulations.

Long non-coding RNAs in stem cells and cancer.

An overwhelming majority of the transcribed genome encodes for non-coding RNA (ncRNA) sequences. Deep sequencing of the transcriptome has uncovered tens of thousands of long ncRNA (lncRNA) sequences. However, little is known regarding the possible functions for a vast majority of these sequences.

Characterization of a stem-like subpopulation in basal-like ductal carcinoma in situ (DCIS) lesions.

Previously, we found that basal-like ductal carcinoma in situ (DCIS) contains cancer stem-like cells. Here, we characterize stem-like subpopulations in a model of basal-like DCIS and identify subpopulations of CD49f+/CD24- stem-like cells that possess aldehyde dehydrogenase 1 activity. We found that these cells show enhanced migration potential compared with non-stem DCIS cells.

The Krüppel-like factor 2 and Krüppel-like factor 4 genes interact to maintain endothelial integrity in mouse embryonic vasculogenesis.

Background: Krüppel-like Factor 2 (KLF2) plays an important role in vessel maturation during embryonic development. In adult mice, KLF2 regulates expression of the tight junction protein occludin, which may allow KLF2 to maintain vascular integrity. Adult tamoxifen-inducible Krüppel-like Factor 4 (KLF4) knockout mice have thickened arterial intima following vascular injury.

Estrogen receptor α signaling regulates breast tumor-initiating cells by down-regulating miR-140 which targets the transcription factor SOX2.

Several reports have indicated that miR-140, a possible tumor suppressor microRNA (miR), is down-regulated in breast tumors compared with normal breast tissues. However, the role of miR-140 in breast tumorigenesis is unclear. We initiated studies that examined estrogen receptor α (ERα) signaling in the tissue-specific regulation of miR-140 in breast cancer.

miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells.

NF-E2-related factor 2 (Nrf2) is an important transcription factor that activates the expression of cellular detoxifying enzymes. Nrf2 expression is largely regulated through the association of Nrf2 with Kelch-like ECH-associated protein 1 (Keap1), which results in cytoplasmic Nrf2 degradation. Conversely, little is known concerning the regulation of Keap1 expression.

MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism.

NF-E2-related factor 2 (Nrf2) is an important transcription factor involved in antioxidant response. Nrf2 binds antioxidant response elements (ARE) within promoters of genes encoding detoxification enzymes (e.g.

miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells.

Evidence supports a critical role for microRNAs (miRNAs) in regulation of tissue-specific differentiation and development. Signifying a disruption of these programs, expression profiling has revealed extensive miRNA dysregulation in tumors compared with healthy tissue. The miR-200 family has been established as a key regulator of epithelial phenotype and, as such, is deeply involved in epithelial to mesenchymal transition (EMT) processes in breast cancer.