The National Institutes of Health handed out nearly $1 million in grant funding over the past few weeks to help fund four research projects examining the role of microRNAs in breast cancer.
The first grant was awarded to the University of Chicago's Dezheng Huo to support his investigations into miRNAs as biomarkers for the detection of triple-negative breast cancer, a form of the disease in which genes for estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 are not expressed.
Amid a need for “novel, non-invasive biomarkers for breast cancer detection and screening,” miRNAs have shown promise as such given their presence in serum and plasma, tissue-specific expression profiles, and ability to be uniformly amplified and quantified, according to Huo's grant abstract.
To further explore this potential, he and his colleagues plan to identify miRNAs in serum that are differentially expressed between 30 triple-negative breast cancers, 30 other types of breast cancer, and 40 matched controls. This work will be followed by a replication study in an independent sample of 60 cases and 40 controls.
“To prioritize and select putative microRNAs, we will also examine the concordance of microRNA levels in the serum and breast tissues of breast cancer patients, and explore their biologic relevance using bioinformatics approaches and experimental validation,” Huo added.
The grant began on Aug. 2 and runs until July 31, 2014. It is worth $206,190 in its first year.
The second grant went to University of Colorado, Denver's David Drasin, who is exploring the role of miR-424 in the epithelial-to-mesenchymal transition, or EMT, of breast cancer.
During EMT, epithelial cells acquire mesenchymal characteristics and lose their epithelial traits, which can result in increased motility and invasiveness, Drasin wrote in his grant's abstract. While EMT is a key part of certain normal processes such as embryogenesis and wound healing, aberrant forms can contribute to cancer metastases.
In previous studies, he and his colleagues found that miR-424 is up-regulated during the active EMT process in human mammary cells at times when mesenchymal markers are increasing, but epithelial markers have not yet been repressed.
“This temporal separation of events suggests there are different regulatory arms of epithelial and mesenchymal programming during an EMT, at least initially,” he noted.
The miRNA was also found to be sufficient to induce mesenchymal-like genes that correlate positively with breast cancer metastasis in vivo without affecting epithelial programming, and to enrich for a tumor-initiation population in vitro, the abstract states.
In light of these data, Drasin aims to determine whether miR-424 is required for mesenchymal features downstream of the EMT inducer and oncogene Twist1 by inhibiting its function. He and his colleagues also plan to examine whether the miRNA's expression correlates with increased aggressiveness in human breast cancers.
“In addition, we will examine whether miR-424 is involved in promoting tumor initiation and breast cancer metastasis itself in vivo, as these properties have been associated with EMT,” he wrote.
The NIH-funded project began Aug. 1 and runs until the end of July, 2015. It is worth $28,752 the first year.
Also receiving NIH support is Zdravka Medarova, a Massachusetts General Hospital researcher developing an miRNA-targeted treatment for lymph node metastatic breast cancer.
According to her grant's abstract, the effort will focus on developing locked nucleic acids that inhibit miR-10b, which has been shown to mediate tumor invasion and breast cancer cell migration, and miR-21, which has been linked to tumor cell proliferation and survival.
In preliminary studies, Medarova and her colleagues have shown that treating breast cancer cells with 1.5 nmol/ml of miR-10b LNA can reduce the miRNA's expression by 88 percent, and prevent both the cells' migration and invasion. In vivo studies, meantime, show that intravenous administration of a tumor-targeted version of the LNA can trigger “robust tumor uptake” and the elimination of tumor cell metastasis from the primary tumor to lymph nodes in mice, the abstract notes.
To extend these early findings, Medarova plans to combine the miR-10b LNA with a miR-21 inhibitor, and examine the therapeutic cocktail's effect on metastatic burden.
Her grant began on Aug. 14 and runs until May 31, 2017. It is worth $396,090 in its first year.
The last grant was awarded to Emily Wang of the City of Hope, who is researching the role of miR-105 in breast cancer metastasis.
Preliminary data suggest that the miRNA, whose levels in the circulation are linked to metastatic progression in early-stage breast cancer patients, is secreted by metastatic breast cancer cells and is known to induce their migration and proliferation, she noted in her grant's abstract.
The miRNA is also found in metastatic breast cancer-secreted exosomes, which have been shown to be internalized and to facilitate metastasis in various tissues, as well as invade normal epithelial and endothelial cells, where the miRNA alters the expression of the tight junction protein ZO-1 and disrupts barrier function between the cell types, she added.
To advance these findings, Wang aims to further investigate the effect of miR-105 on cancer cell adhesion, migration, invasion, proliferation, and anchorage-independent growth, as well as the role of ZO-1 in mediating these effects, the abstract states. Additionally, other miR-105-regulated genes will be identified and their role in mediating the miRNA's effects will be determined.
Next, she plans to determine the effects of cancer-secreted, exosome-transferred miR-105 on normal epithelial and endothelial niche cells, focusing on how their cellular barrier-disruption effects restrict cancer cell invasion and metastasis, the abstract adds. “The magnitude and kinetics of miR-105-mediated barrier-destroying effects will be determined by co-culturing the epithelial and endothelial niche cells with [metastatic breast cancer] cells that secrete miR-105.”
Finally, the effects of miR-105 on niche adaptation and breast cancer metastasis will be examined in mouse xenograft models, with the goal of establishing a proof of concept for therapeutically targeting cancer-excreted miRNAs.
Wang's project began on Sept. 1 and is worth $348,600 the first year. It runs until June 30, 2017.