Team
discovers new inhibitors of estrogen-dependent breast cancer
cells
Researchers have discovered a new family of agents
that inhibit the growth of estrogen-dependent breast
cancer cells. The finding, described today at a
meeting of the Endocrine Society, has opened an avenue
of research into new drugs to combat
estrogen-dependent breast cancers.
“This cell-based study is exciting because it suggests
these compounds are likely to be effective in tumors
that remain dependent on estrogen for growth but are
resistant to current therapies,” said principal
investigator David J. Shapiro, a professor of
biochemistry in the School of Molecular and Cellular
Biology at the University of Illinois.
Although multiple factors contribute to the
development of breast cancer, estrogens play a key
role in the growth of many tumors. More than 80
percent of breast cancer tumors in women over age 45
are activated by estrogen by way of a protein called
an estrogen receptor. When estrogen binds to the
receptor, this “estrogen-receptor complex” latches on
to DNA and prompts it to transcribe the RNA blueprints
for new proteins that promote cell growth, migration
and division.
Current therapies for estrogen-receptor-positive
(ER-positive) breast cancers include the use of drugs,
such as tamoxifen, that interfere with estrogen’s
ability to bind to the estrogen receptor. Over time,
however, ER-positive breast cancer tumors become
resistant to tamoxifen. In some resistant tumors,
tamoxifen even begins to act like estrogen and
actually stimulates tumor growth.
“Tamoxifen is useful in that it is very effective at
blocking recurrence of breast cancer in patients for
whom the entire tumor is removed,” Shapiro said. “But
for patients who still have existing tumors,
eventually those tumors will become resistant.”
Shapiro’s team sought to target other steps in the
pathway of estrogen action. Using a technique they
developed that can quickly determine whether the
target DNA is – or is not – bound by the
estrogen-receptor complex, the team was able to screen
a long list of potential therapeutic compounds to see
if they inhibited the binding of the complex to the
DNA. They then tested these agents in ER-positive
breast cancer cells.
The team identified several compounds that reduce the
binding of estrogen-receptor complex to the regulatory
regions of genes that are normally activated by this
complex. These agents effectively retarded production
of the proteins that promote the growth and
proliferation of ER-positive breast cancer cells.
“These small molecules specifically block growth of
estrogen-dependent breast cancer cells with little or
no effect on other cells,” Shapiro said. “This work
sets the stage for further development and testing of
these inhibitors.”
The collaboration included researchers from the
University of Colorado, the University of North
Carolina, and the departments of molecular and
integrative physiology and of chemistry at Illinois.
This basic research study was supported by the
National Institute of Diabetes and Digestive and
Kidney Diseases at the National Institutes of Health.
Source:-
University of Illinois at Urbana-Champaign
