Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer.

Abstract

In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.

• Authors: Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, Guido Kroemer
• Journal: Autophagy (Autophagy) Vol. 11 Issue 10 Pg. 1878-90 ( 2015) ISSN: 1554-8635 [Electronic] United States
• PMID: 26506894 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• HMGB1 Protein
• MAP1LC3B protein, human
• Microtubule-Associated Proteins

Topics

• Autophagy (genetics, physiology)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (pathology, therapy)
• Chemotherapy, Adjuvant (methods)
• Female
• Gene Expression Regulation, Neoplastic (physiology)
• HMGB1 Protein (metabolism)
• Humans
• Microtubule-Associated Proteins (metabolism)
• Recurrence
• Risk Factors