UC Researchers Find Protein That Mediates Formation of HER2 Breast Cancer
Published: 1/9/2018
CINCINNATI—Researchers at the University of Cincinnati
College of Medicine have identified for the first time that the
estrogen receptor-binding protein MED1 is a critical mediator of
HER2-driven breast cancer, identifying it as a potential
therapeutic target.
MED1 is a protein often produced, or expressed, at abnormally
high levels in breast cancer cells that when eliminated is found to
stop cancer cell growth; HER2 breast cancer involves a protein
called human epidermal growth factor receptor 2, which promotes the
growth of cancer cells.
These findings, published ahead of print in the Jan. 8 online
edition of the journal
Cancer Research, could
lead to better, more effective treatments 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, associate professor in the Department of
Cancer Biology at the UC College of Medicine, member of the
Cincinnati Cancer Center and the UC Cancer Institute and lead
author on this study. "Studies have divided breast cancer into
several subtypes based on gene expression of estrogen receptor,
progesterone receptor and/or HER2. MED1 is an estrogen receptor
coactivator that has been shown to play important roles in estrogen
receptor-dependent functions in both mammary gland development 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 in this study, researchers generated animal models
with the HER2 cancer gene and the mutation of MED1 to evaluate the
protein’s role in breast cancer progression and spread.
"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 first evidence indicating that MED1 and its LxxLL motifs play a
critical role in breast cancer formation, metastasis and cancer
stem cell formation. This is also the first time a gene
co-amplified with HER2 has been shown to play a role in HER2-driven
cancer formation. Further investigations looking at the mechanisms
underlying MED1 functions revealed that it acted directly to
regulate estrogen signaling through the downstream IGF-1 pathway, a
key pathway known to play critical roles in breast cancer.
Importantly, human breast cancer patient samples showed a strong
correlation between MED1 and IGF-1 protein levels, further
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.”
Along with Zhang, the first author of the study is Yongguang
Yang, PhD, research associate in the Department of Cancer Biology.
Co-authors on the study include Marissa Leonard and Yijuan Zhang,
PhD, from Zhang’s lab; Elyse Lower, MD, and Charif Mahmoud,
MD, from the hematology oncology division in the Department of
Internal Medicine; and Shagufta Khan, MD, and Jiang Wang, MD, PhD,
from the Department of Pathology.
This study was funded by Ohio Cancer Research seed money,
Cincinnati Cancer Center and UC Cancer Institute pilot grants, Ride
Cincinnati, a Komen for the Cure Foundation Career Catalyst Grant
(KG110028), an American Cancer Society Research Scholar Grant
(RSG-12-268-01) and the National Institutes of Health
(R01CA197865).
Zhang cites no conflict of interest.
Back to News