Wwox inactivation enhances mammary tumorigenesis
Date
2011-04-18
Authors
Abdeen, SK
Salah, Z
Maly, B
Smith, Y
Tufail, R
Abu-Odeh, M
Zanesi, N
Croce, CM
Nawaz, Z
Aqeilan, RI
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Publishing Group
Abstract
Breast cancer is the leading cause of cancer-related death
in women worldwide. Expression of the WWOX tumor
suppressor is absent or reduced in a large proportion of
breast tumors suggesting that loss of WWOX may
contribute to breast tumorigenesis. Wwox-deficient mice
die by 3–4 weeks of age precluding adult tumor analysis.
To evaluate the effect of WWOX-altered expression on
mammary tumor formation, the Wwox-heterozygous allele
was back crossed onto the C3H mammary tumor-susceptible
genetic background (WwoxC3Hþ/ ) and incidence of
mammary tumor formation was evaluated. Although 50%
of the female WwoxC3Hþ/ mice developed mammary carcinomas,
only 7% of WwoxC3Hþ/þ mice did. Intriguingly,
mammary tumors in WwoxC3Hþ/ mice frequently lost
WWOX protein expression suggesting a genetic predisposition
toward mammary tumorigenesis. Immunohistochemical
staining of hormone receptors revealed loss
of estrogen receptor-a (ER) and progesterone receptor in
the majority of these tumors. In vitro, depletion ofWWOX
in MCF7 ER-positive cells led to reduced ER expression
and reduced sensitivity to tamoxifen and estrogen treatment
and was associated with enhanced survival and anchorageindependent
growth. Finally, cDNA array analyses of murine
normal mammary epithelial cells and mammary tumors
identified 163 significantly downreguated and 129 upregulated
genes in the tumors. The majority of differentially
expressed genes were part of pathways involved in cellular
movement, cell-to-cell signaling and interaction, cellular
development, cellular growth and proliferation and cell death.
These changes in gene expression of mouse mammary
tumors in WwoxC3Hþ/ mice resemble, at least in part,
human breast cancer development. Our findings demonstrate
the critical role that the WWOX tumor suppressor
gene has in preventing tumorigenesis in breast cancer.
Description
Keywords
WWOX , WW domains , breast cancer , triple negative , tumor suppressor