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richessewoozyΒιοτεχνολογία

1 Οκτ 2013 (πριν από 4 χρόνια και 1 μήνα)

101 εμφανίσεις

CD73: a new target for triple
-
negative breast cancer

Sherene Loi
1
, Sandra Pommey
2
, Benjamin Haibe
-
Kains
3
, Paul A. Beavis
4
, Phillip K. Darcy
4, 5
,
Mark J. Smyth
4, 5
, and
John Stagg

2
.

1
Breast Cancer Translational Research Laboratory (BCTL) J.C.
Heuson, Institut Jules Bordet,
Boulevard de Waterloo, 125, 1000 Brussels, Belgium.

2
Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Faculté de Pharmacie
et Institut du Cancer de Montréal, Montréal, Québec, Canada, H2L 4M1.

3
Bioinformatics and Computational Genomics Laboratory, Institut de recherches cliniques de
Montréal, Montréal, Canada

4
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St.
Andrews Place, East Melbourne, Victoria 3002, Au
stralia.

5
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3010,
Australia.


Triple negative breast cancer (TNBC),
as
defined by the absence of estrogen receptor (ER),
progesterone receptor (PR) and HER2 expression, accounts

for 15
-
20% of all breast cancers

and
is
characterized by a worse prognosis
compared to other
subtypes

of breast cancer
. Importantly,
t
here are currently no known molecular targets for this subgroup of breast cancer patients
.
Using
gene expression data from over 6,000 breast cancer patients, we
discovered

that high CD73
expression is associated with a poor prognosis in
TNBC patients

and positively correlated with
metastasis
-
associated gene
s.
As anthracycline
-
based chemotherapy
regimens are standard
treatment for TNBC, we investigated the relationship between CD73 and anthracycline efficacy.
Strikingly, i
n TNBC patients treated with doxorubicin (DOX)
-
only neoadjuvant chemotherapy, high
CD73 gene expression was significantly assoc
iated with a lower rate of pathological complete
response at surgery. Using mouse models of
TNBC
, we demonstrated that
CD73 overexpression
in tumor cells
confers

chemoresistance to anthracycline by suppressing adaptive anti
-
tumor
immune responses via activ
ation of A2A adenosine receptors. Combining DOX with targeted
blockade of CD73

induced potent anti
-
tumor immune responses against TNBC and significantly
prolonged the survival of mice with established metastatic disease. Taken together, our data
suggest th
at CD73 constitutes a new therapeutic target in TNBC.

We acknowledge funding
support from the Susan G. Komen for the Cure, the National Health and Medical Research
Council (NH&MRC) of Australia (1013667, 1007902), the Victorian Cancer Agency (EOI09_71),
th
e Canadian Institutes of Health Research and the Cancer Research Society of Canada.

Contact
author
: John Stagg


john.stagg@umontreal.ca.