A University of Cincinnati (UC) cancer biology team reports breakthrough
findings about specific cellular mechanisms that may help overcome
endocrine (hormone) therapy-resistance in patients with
estrogen-positive breast cancers, combating a widespread problem in
effective medical management of the disease.
Xiaoting Zhang, PhD, and his colleagues have identified a specific
estrogen receptor co-activator -- known as MED1 -- as playing a central
role in mediating tamoxifen resistance in human breast cancer. The team
reports its findings in the Nov. 1, 2012, issue of Cancer Research, a scientific journal of the American Association for Cancer Research.
According to the National Cancer Institute, nearly 227,000 women are
diagnosed with breast cancer annually in the United States. About 75
percent have estrogen-positive tumors and require adjuvant hormone
therapy such as tamoxifen, a drug that works by interfering with
estrogen's ability to stimulate breast cancer cell growth.
Despite advances in hormone therapy drugs, cancer surveillance
research has shown that 50 percent of patients will develop resistance
to the drug and experience a cancer relapse.
The hormones estrogen and progesterone can stimulate the growth of
some breast cancers. Hormone therapy is used to stop or slow the growth
of these tumors. Hormone-sensitive (i.e., positive) breast cancer cells
contain specific proteins known as hormone receptors that become
activated once hormones bind to them, leading to cancer growth.
Based on new findings, UC Cancer Institute scientists believe that
tamoxifen resistance may be driven by a novel molecular "crosstalk"
point between the estrogen and HER2 (human epidermal growth factor
receptor 2) signaling pathways.
Testing in both pre-clinical models and human breast cancer tissue
samples showed that MED1 co-amplifies and co-expresses with HER2, a gene
that has an increased presence in 20-30 percent of invasive human
breast cancer and plays a major role in tamoxifen resistance.
HER2 over-expression led to MED1 activation while reduction of MED1
caused breast cancer cells that were otherwise tamoxifen-resistant to
respond and stop dividing. Further mechanistic studies showed that HER2
activation of MED1 resulted in the recruitment of co-activators instead
of co-repressors by tamoxifen-bound estrogen receptor. This, explains
Zhang, drives expression of not only traditional estrogen
receptor-positive cancer target genes, but also HER2 and those estrogen
receptor target genes abnormally activated by HER2.
"Together, these findings suggest this 'crosstalk' could play a
central role in mediating tamoxifen resistance in human breast cancer,
especially because recent published data also indicated that high MED1
expression levels correlate with poor treatment outcome and disease-free
survival of patients who underwent endocrine therapy," explains Zhang,
an assistant professor of cancer biology at the UC College of Medicine
and breast cancer researcher with the UC Cancer Institute.
"We are currently utilizing RNA-based nanotechnology to target MED1
in an effort to simultaneously block both estrogen and HER2 pathways to
overcome endocrine-resistant breast cancer."
UC study collaborators include cancer biologists Jiajun Cui, PhD,
Katherine Germer, MD, Shao-chun Wang, PhD; environmental health
researcher Tianying Wu, PhD; and pathologist Jiang Wang, MD. Qianben
Wang, PhD of the Ohio State University College of Medicine, and Jia Luo,
PhD, of the University of Kentucky, also contributed to this study.
The study was supported with start-up funding from the UC Cancer
Institute, Ride Cincinnati/Marlene Harris Pilot Grant, Susan G. Komen
for the Cure Foundation and the Center for Clinical and Translational
Science and Training -- home to UC's institutional Clinical and
Translational Science Award program grant from the National Institutes
of Health.
Journal Reference:
- J. Cui, K. Germer, T. Wu, J. Wang, J. Luo, S.-c. Wang, Q. Wang, X. Zhang. Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells. Cancer Research, 2012; 72 (21): 5625 DOI: 10.1158/0008-5472.CAN-12-1305
Courtesy: ScienceDaily
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