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Erschienen in:
19.05.2020 | Original paper
RETRACTED ARTICLE: Downregulation of beta-catenin in chemo-tolerant TNBC through changes in receptor and antagonist profiles of the WNT pathway: Clinical and prognostic implications
Erschienen in: Cellular Oncology | Ausgabe 4/2020
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Purpose
In approximately 30% of triple-negative breast cancer (TNBC)
patients a complete pathological response is achieved. However, after
neo-adjuvant chemotherapy treatment (NACT) residual tumour cells can be
intrinsically resistant to chemotherapy. In this study, associations of the
WNT/beta-catenin pathway with chemo-tolerance of NACT treated TNBC patients were
compared to that of pre-treatment TNBC patients.
Methods
Expression analyses were performed in both pre-treatment and NACT
treated TNBC samples using immunohistochemistry and qRT-PCR, along with DNA copy
number variation (CNV) and promoter methylation analyses to elucidate the
mechanism(s) underlying chemo-tolerance. In addition, in vitro validation
experiments were performed in TNBC cells followed by in vivo clinicopathological
correlation analyses.
Results
A reduced expression (41.1%) of nuclear beta-catenin together with
a low proliferation index was observed in NACT samples, whereas a high
expression (59.0%) was observed in pre-treatment samples. The reduced nuclear
expression of beta-catenin in the NACT samples showed concordance with reduced
expression levels (47-52.9%) of its associated receptors (FZD7 and LRP6) and
increased expression levels (35.2–41.1%) of its antagonists (SFRP1,
SFRP2, DKK1) compared to those in the pre-treatment samples. The expression
levels of the receptors showed no concordance with its respective gene copy
number/mRNA expression statuses, regardless treatment. Interestingly, however,
significant increases in promoter hypomethylation of the antagonists were
observed in the NACT samples compared to the pre-treatment samples. Similar
expression patterns of the antagonists, receptors and beta-catenin were observed
in the TNBC-derived cell line MDA-MB-231 using the anthracyclines doxorubicin
and nogalamycin, suggesting the importance of promoter hypomethylation in
chemotolerance. NACT patients showing reduced receptor and/or beta-catenin
expression levels and high antagonist expression levels exhibited a
comparatively better prognosis than the pre-treatment patients.
Conclusions
Our data suggest that reduced nuclear expression of beta-catenin in
NACT TNBC samples, due to downregulation of its receptors and upregulation of
its antagonists through promoter hypomethylation of the WNT pathway, plays an
important role in chemo-tolerance.
