MT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib

• Published in: British journal of cancer 2017-03, Vol.116 (6), p.742-751
• Main Authors: Yip, Cassandre, Foidart, Pierre, Somja, Joan, Truong, Alice, Lienard, Mehdi, Feyereisen, Emilie, Schroeder, Hélène, Gofflot, Stéphanie, Donneau, Anne-Françoise, Collignon, Joëlle, Delvenne, Philippe, Sounni, Nor Eddine, Jerusalem, Guy, Noël, Agnès
• Format: Article
• Language: English
• Subjects: 631/45/612/1237; 692/699/67/1347; 692/699/67/1857; 692/700/565/1436/99; Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Biomarkers; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cancer therapies; Chemotherapy; Clinical trials; Drug Resistance; Epidemiology; Epidermal growth factor; Epirubicin - administration & dosage; Erlotinib Hydrochloride - administration & dosage; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Immunotherapy; Kinases; Life sciences; Lymphatic Metastasis; Matrix Metalloproteinases, Membrane-Associated - metabolism; Medical prognosis; Medical research; Mice; Mice, Nude; Middle Aged; Molecular Medicine; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplasm Staging; Oncology; Patients; Prognosis; Receptor, Epidermal Growth Factor - metabolism; Retrospective Studies; Sciences du vivant; Survival Rate; Translational Therapeutics; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/bjc.2017.23

Background: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC. Methods: We conducted a retrospective immunohistochemical analysis on human TNBC samples ( n =81) and validated our findings in in vitro and in vivo assays. Results: Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro . In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours. Conclusions: We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs.