Silencing the speech gene...

wallycat

It
is an intricate network of activity that enables breast cancer cells to
move from the primary breast tumor and set up new growths in other
parts of the body, a process known as metastasis.

Now a research team led by investigators at Beth Israel Deaconess
Medical Center (BIDMC) has identified an unexpected link between a
transcription factor known to regulate speech and language development
and metastatic colonization of breast cancer.

Currently described online in Cell Stem Cell, the new
findings demonstrate that, when silenced, the FOXP2 transcription
factor, otherwise known as the speech gene, endows breast cancer cells
with a number of malignant traits and properties that enable them to
survive -- and thrive.

"We have identified a previously undescribed function for the
transcription factor FOXP2 in breast cancer," explains senior author
Antoine Karnoub, PhD, an investigator in the Department of Pathology at
BIDMC and Assistant Professor of Pathology at Harvard Medical School.
"We have found that depressed FOXP2 [a member of the forkhead family of
transcriptional regulators] and elevated levels of its upstream
inhibitor microRNA 199a are prominent features of clinically advanced
breast cancers that associate with poor patient survival."

Karnoub's lab investigates the roles that mesenchymal stem cells
(MSCs) play in the development and metastasis of breast cancer. MSCs are
adult progenitor cells that function as the body's early responders,
poised to take action to help repair damaged tissues, jumping from their
niches in the bone, for example, into the blood, migrating to areas of
inflammation, and orchestrating the body's reactions during wound
healing. Previous work by Karnoub revealed that MSCs respond to breast
tumors akin to the way they react to a wound or infection and that these
cells participate in the formation of the breast tumor stroma, the
supporting network of cells and their secretions that exist in the
microenvironment of cancer cells.

"We think that by direct actions on the cancer cells and by
manipulating other cells in the microenvironment, MSCsend up providing
cancer cells with better abilities to survive and a safe haven in which
to thrive," says Karnoub. Despite expanding knowledge of the role of
MSCs to breast malignancy, the underlying molecular responses of breast
cancer cells to MSC influences has not been fully delineated. In this
new paper, the investigators set out to specifically identify the role
that microRNAs were playing in the process.

miRNAs are short noncoding RNAs that play critical functions in
cancer pathogenesis,. "An expanding body of evidence has documented
miRNA deregulation in multiple aspects of tumor development, including
invasion and metastasis," says Karnoub. The induction by MSCs of one
such miRNA, miR199a, facilitated the acquisition of malignant properties
by the cancer cells, including cancer stem cell and metastatic traits.
(Cancer stem cells are thought to be the most virulent cells that lie
within the core of most tumors, and are believed to be responsible for
the resurgence of tumors following chemotherapy treatment.)

"After we found that miRNA-199a instigated in the cancer cells by
MSCs was indeed promoting these cancer stem cells phenotypes and was
facilitating cancer metastasis, we probed the mechanistic details of
miR-199a's actions, " explains Karnoub. "miRNAs function predominantly
by suppressing target mRNA expression, and we analyzed an overwhelming
majority of the published targets that have been associated with these
miRNAs, but none was repressed in our systems. We then made a screen and
serendipitously fished out a gene called FOXP2." At that time, he adds,
basically nothing was known about this protein in relation to breast
cancer.

FOXP2 has primarily been implicated in regulating speech and language
development and several reports have described functions for this
protein in developmental neurogenesis. Additional reports have also
linked FOXP2 to tissue development, such as the lung.

"We were curious and wanted to find out the business of FOXP2 in
breast cancer," he adds. "Surprisingly, we found that its suppression in
the tumor cells was sufficient to expand cancer stem cell traits and
caused the cancer cells to metastasize much more vigorously."

These findings agreed with similar results in which the authors
determined that miR-199a upregulation and FOXP2 repression are prominent
features of aggressive clinical breast cancers and represent
independent prognostic parameters for overall patient survival.

"We are one step closer to understanding how cells in the tumor
microenvironment, such as MSCs, promote the malignancy of neighboring
cancer cells," says Karnoub. "We're now more closely investigating
FOXP2's potential role as a metastasis suppressor that needs to be
downregulated for metastasis to take place."

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Story Source:

The above story is based on materials provided by Beth Israel Deaconess Medical Center. Note: Materials may be edited for content and length.

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Journal Reference:

1. Benjamin G. Cuiffo, Antoine Campagne, George W. Bell, Antonio Lembo,
   Francesca Orso, Evan C. Lien, Manoj K. Bhasin, Monica Raimo, Summer E.
   Hanson, Andriy Marusyk, Dorraya El-Ashry, Peiman Hematti, Kornelia
   Polyak, Fatima Mechta-Grigoriou, Odette Mariani, Stefano Volinia, Anne
   Vincent-Salomon, Daniela Taverna, Antoine E. Karnoub. MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis. Cell Stem Cell, 2014; DOI: 10.1016/j.stem.2014.10.001