complex provides new target for thwarting cancer migration, invasion
molecular machinery that switches on a gene known to cause
breast cancer to spread and invade other organs has been
identified by an international team led by scientists at
The University of Texas M. D. Anderson Cancer Center. The
paper was published in Nature Cell Biology™s advanced online
provides a target-rich environment for development of drugs to
thwart expression of the RhoA gene, according to Hui-Kuan Lin,
Ph.D., the paper's senior author and an assistant professor in
M. D. Anderson's Department of Molecular and Cellular Oncology.
RhoA overexpression has been implicated in cancer metastasis.
four components to this complex, which starts RhoA expression
by transcribing the gene, and we found that all of them are important
to metastasis," Lin said. "Knock down any one of the four, and
you can stop breast cancer metastasis by preventing RhoA expression."
built their case with a series of laboratory experiments on cell
lines, followed by confirmation in a mouse model of breast cancer
metastasis and then analysis of 64 prostate cancer tumors that
showed overexpression of RhoA or three of its transcription complex
components were strongly correlated with metastatic disease.
is the first step on a gene's path to expressing its protein.
Transcription factors bind to the promoter region of the gene,
causing a copy of RNA to be made from the DNA of the gene. The
RNA is then translated into the corresponding protein.
The team first
established the Myc protein as a transcription factor that binds
to RhoA's promoter region. Knocking down Myc in cancer cell lines
decreased RhoA expression, cell migration and invasion, while
Myc overexpression increased all three.
found that the Skp2 overexpression also results in more RhoA,
and that both Skp2 and Myc were required for the metastasis-producing
RhoA to be overexpressed.
pathway is the second way Skp2 fuels cancer growth, Lin said.
Skp2 has been shown to work through a separate E3 ligase pathway
to destroy tumor-suppressing proteins, causing heightened cellular
proliferation and the transition from normal cell to tumor.
ligase activity is required for tumorigenesis, but not involved
at all in metastasis," Lin said. Lin and colleagues also previously
found that Skp2 blocks cellular senescence – a halt in cell division
– in cancer cells.
team then found that Skp2 recruits two other proteins, p300 and
Miz1, to join Myc and form the complex that transcribes RhoA.
in a mouse model of breast cancer metastasis to the lung showed
that deficiency of either Myc, Skp2 or Miz1 restricted metastasis,
while overexpression of each of the three proteins increased cell
migration and invasion. Skp2 knockdown, for example, resulted
in no metastatic nodules in the lung, compared with an average
of 40 nodules when Skp2 was expressed.
down RhoA expression produced the same effect as blocking the
Myc-Skp2-Miz1 complex. Knocking down expression of p300 resulted
in decreased expression of RhoA.
In the analysis
of prostate cancer tumors, expression of RhoA, Myc, Skp2 and Miz1
were significantly correlated with metastasis. Expression of the
RhoA and the Myc-Skp2-Miz1 complex also were highly correlated.
Lin and colleagues
note that Miz1 is thought to be a tumor-suppressor that contends
with the oncogene Myc to regulate genes. In this case, the tumor-suppressor
cooperates with the oncogene to launch RhoA and promote metastasis.
there are no small-molecule agents to inhibit any of these targets,"
Lin said. "One future direction of research will be to find ways
to target the entire transcription complex or its individual components."
this research comes from M. D. Anderson's Research Trust Scholar
funds, The National Cancer Institute's Prostate Cancer Specialized
Program in Research Excellence at M. D. Anderson and a Department
of Defense New Investigator Award to Lin.
to Lin, other co-authors from M. D. Anderson's Department of Molecular
and Cellular Oncology include: first author Chia-Hsin Chan, M.D.;
Szu-Wei Lee, also also a graduate student in The University of
Texas Graduate School of Biomedical Sciences at Houston; Jing
Wang, Ph.D.; Wei-Lei Yang, M.D., Ching-Yuan Wu, M.D., also with
Chang Gung Memorial Hospital-Kaohsiung Medical Center and Chang
Gung University College of Medicine, Taiwan, Juan Wu, also with
State Key Laboratory of Oncology in South China and Sun Yat-Sen
University Cancer Center; and Mien-Chie Hung, Ph.D., department
chair, also on the faculty of The University of Texas Graduate
School of Biomedical Sciences at Houston, and Center for Molecular
Medicine and Graduate Institute of Cancer Biology at China Medical
University and Hospital, Taiwan. Other authors include: Chien-Feng
Li, M.D., Department of Pathology at Chi-Mei Medical Center; Keiichi
I. Nakayama, M.D., Ph.D., Medical Institute of Bioregulation at
Kyushu University at Fukuoka, Japan; Hong-Yo Kang, Ph.D., and
Hsuan-Ying Huang, M.D, Graduate Institute of Clinical Medical
Sciences at Chang Gung Memorial Hospital-Kaohsiung Medical Center,
Chang Gung University College of Medicine; Pier Paolo Pandolfi,
M.D., Ph.D., Cancer Genetics Program at Beth Israel Deaconess
Cancer Center and Department of Medicine and Pathology at Beth
Israel Deaconess Medical Center at Harvard Medical School.
of Texas M. D. Anderson Cancer Center in Houston ranks as one
of the world's most respected centers focused on cancer patient
care, research, education and prevention. M. D. Anderson is one
of only 40 comprehensive cancer centers designated by the National
Cancer Institute. For six of the past eight years, including 2009,
M. D. Anderson has ranked No. 1 in cancer care in "America's Best
Hospitals," a survey published annually in U.S. News & World