Downregulation of beta-catenin in chemo-tolerant TNBC through changes in receptor and antagonist profiles of the WNT pathway: Clinical and prognostic implications.

Abstract

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.

• Authors: Saimul Islam, Hemantika Dasgupta, Mukta Basu, Anup Roy, Neyaz Alam, Susanta Roychoudhury, Chinmay Kumar Panda
• Journal: Cellular oncology (Dordrecht) (Cell Oncol (Dordr)) Vol. 43 Issue 4 Pg. 725-741 (Aug 2020) ISSN: 2211-3436 [Electronic] Netherlands
• PMID: 32430683 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• CTNNB1 protein, human
• beta Catenin

Topics

• Adult
• Aged
• Antineoplastic Agents (therapeutic use)
• DNA Methylation (genetics)
• Down-Regulation
• Drug Resistance, Neoplasm (physiology)
• Female
• Humans
• Middle Aged
• Neoadjuvant Therapy
• Prognosis
• Triple Negative Breast Neoplasms (drug therapy, genetics, metabolism)
• Wnt Signaling Pathway (physiology)
• beta Catenin (metabolism)