Men who get melanoma are twice as
likely to die from the disease as women. However, the biological explanation for
this is poorly understood.
Research led by Dr. Alan Spatz, Director of
Surgical and Molecular Pathology at the Jewish General Hospital and head
of the "X chromosome and cancer" lab at the Lady Davis Institute in
Montreal, reveals that the decreased expression of the X chromosome gene
PPP2R3B and its protein PR70 are positively linked to tumor progression
in this aggressive form of skin cancer.
‘The decreased expression of the X chromosome gene PPP2R3B and its protein PR70 are positively linked to tumor progression in melanoma.’
The finding is published in Science Translational Medicine
"We focused our research on the machinery of the X chromosome
because we postulated that the inactivation of one of the two X
chromosomes in women, as opposed to men who have an X and a Y, and the
way this mechanism is regulated, may have deep implications on the cell
biology of cancer cells" explains Dr. Spatz, who has a long-standing
interest in the role of the X chromosome in cancer.
"I proposed in 2004 a
theoretical model of X-linked tumor suppressor genes loss and oncogenes
activation that since has been validated in many situations. The fact
that two X's interact together in females has also implications for
cancer. We believe that the genetic specificity of the X chromosome
plays a significant function in the gender difference we observe in
melanoma. And we see unique regulation of tumor suppressor genes and
oncogenes in the X chromosome."
Dr. Spatz, Professor of Pathology and Oncology at McGill University,
and Dr. Leon van Kempen, COO and Scientific Director Molecular
Pathology Center, have extensively studied the gene PPP2R3B, which is
located on the X chromosome in females, but on the Y in males.
expression of this gene has been independently correlated with more
favorable progression in melanoma and is important because its
expression is higher in females. PPP2R3B codes for the PR70 protein,
which decreases melanoma growth by negatively interfering with DNA cell
replication and, therefore, acting as an X-linked tumor suppressor.
PR70 is at the forefront of controlling the cell replication
cascade. From a clinical perspective, this research suggests there could
be potential anti-cancer therapies in actioning the proteins linked to
PR70. The proteomics capabilities that have been developed at the Segal
Cancer Center and Lady Davis Institute at the Jewish General Hospital
will eventually be instrumental in profiling and identifying the active
proteins that could be most effectively targeted by novel therapies.
"I believe this discovery advances our understanding of the specific
role of the X chromosome genetics in modulating the expression of genes
that are critical in cancer progression," Dr. Spatz said.
"Specifically, this is a new avenue for exploring X-linked tumor
suppressor genes and oncogenes. I'm confident that we will eventually be
able to exploit this discovery to pursue new therapeutic avenues