Researchers on the University of Cincinnati College of Medicine have recognized for the primary time that the estrogen receptor-binding protein MED1 is a crucial mediator of HER2-driven breast cancer, figuring out it as a possible therapeutic goal.
MED1 is a protein typically produced, or expressed, at abnormally excessive ranges in breast cancer cells that when eradicated is discovered to cease cancer cell progress; HER2 breast cancer includes a protein referred to as human epidermal progress issue receptor 2, which promotes the expansion of cancer cells.
These findings, revealed forward of print within the Jan. eight on-line version of the journal Cancer Research, might result in higher, simpler remedies for aggressive and treatment-resistant breast cancer.
“Breast cancer remains one of the most common cancers and is one of the leading causes of death for women in the U.S.,” says Xiaoting Zhang, PhD, affiliate professor within the Department of Cancer Biology on the UC College of Medicine, member of the Cincinnati Cancer Center and the UC Cancer Institute and lead writer on this research. “Studies have divided breast cancer into a number of subtypes based mostly on gene expression of estrogen receptor, progesterone receptor and/or HER2. MED1 is an estrogen receptor coactivator that has been proven to play essential roles in estrogen receptor-dependent features in each mammary gland improvement and breast cancer.
“Interestingly, the MED1 gene is located very close to and amplified together with HER2 in the gene, and the MED1 protein levels are highly linked to HER2-positive breast cancer. Additionally, we’ve found that HER2 can activate MED1, and MED1 functions as a key ‘crosstalk’ point between the HER2 and estrogen receptor pathway in the treatment resistance of HER2 and estrogen receptor double positive breast cancer. However, the role and underlying molecular functions of MED1 in HER2-driven breast cancer development and spread is still poorly understood.”
Zhang says on this research, researchers generated animal fashions with the HER2 cancer gene and the mutation of MED1 to guage the protein’s position in breast cancer development and unfold.
“The estrogen receptor specifically binds the MED1 protein in the regions known as the LxxLL motifs. We found that mutating MED1 in the LxxLL motifs disrupted its interaction with the estrogen receptor and significantly delayed tumor growth, spread and cancer stem-like cell formation in this model,” Zhang says. “This is the primary proof indicating that MED1 and its LxxLL motifs play a essential position in breast cancer formation, metastasis and cancer stem cell formation. This can also be the primary time a gene co-amplified with HER2 has been proven to play a task in HER2-driven cancer formation. Further investigations wanting on the mechanisms underlying MED1 features revealed that it acted instantly to manage estrogen signaling by way of the downstream IGF-1 pathway, a key pathway recognized to play essential roles in breast cancer. Importantly, human breast cancer affected person samples confirmed a robust correlation between MED1 and IGF-1 protein ranges, additional supporting the potential of MED1 and its LxxLL motifs as therapeutic targets.
“With these findings and our previously published study showing a tissue-specific role for MED1, we can now conduct further studies on MED1 as a disease-selective therapeutic target. Our team is currently using an RNA nanotechnology-based approach to select RNA aptamers (RNA molecules that bind to a specific target molecule) to specifically target MED1 LxxLL motifs to disrupt the MED1/estrogen receptor interactions to achieve this.”
New finding gives clues for overcoming tamoxifen-resistant breast cancer