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

Yip, Cassandre; Foidart, Pierre; Somja, Joan; Truong, Alice; Lienard, Mehdi; Feyereisen, Émilie; Schroeder, Hélène; Gofflot, Stéphanie; Donneau, Anne‐Françoise; Collignon, Joëlle; Delvenne, Philippe; Sounni, Nor Eddine; Jérusalem, Guy; Noël, Agnès

doi:10.1038/bjc.2017.23

Cited by 16 publications

(22 citation statements)

References 38 publications

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“…It was initially characterized as an interstitial collagenase which degraded ECM by directly cleaving its substrate and activating a secretory matrix metalloprotease, MMP-2 (Ohuchi et al, 1997;Sato et al, 1994;Al-Raawi et al, 2011;Clark et al, 2007). Although other membrane-type metalloproteases are also involved in cancer metastasis, their molecular role in ECM remodeling is less explored (Wells et al, 2015;Tatti et al, 2011Tatti et al, , 2015Shen et al, 2017;Yip et al, 2017;Huang et al, 2009;Wu et al, 2017;Jiang et al, 2017). MT2-MMP is overexpressed in breast cancer and is involved in basement membrane transmigration in breast cancer (Kousidou et al, 2004;Benson et al, 2013;Hotary et al, 2006;Ota et al, 2009), but the molecular mechanism governing its role in cancer metastasis is unexplored.…”

Section: Mt1-mmp-mediated Ecm Degradationmentioning

confidence: 99%

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

Sharma

Parveen

Shah

et al. 2019

Journal of Cell Biology

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A variety of metastatic cancer cells use actin-rich membrane protrusions, known as invadopodia, for efficient ECM degradation, which involves trafficking of proteases from intracellular compartments to these structures. Here, we demonstrate that in the metastatic breast cancer cell line MDA-MB-231, retromer regulates the matrix invasion activity by recycling matrix metalloprotease, MT1-MMP. We further found that MT2-MMP, another abundantly expressed metalloprotease, is also invadopodia associated. MT1- and MT2-MMP showed a high degree of colocalization but were located on the distinct endosomal domains. Retromer and its associated sorting nexin, SNX27, phenocopied each other in matrix degradation via selectively recycling MT1-MMP but not MT2-MMP. ITC-based studies revealed that both SNX27 and retromer could directly interact with MT1-MMP. Analysis from a publicly available database showed SNX27 to be overexpressed or frequently altered in the patients having invasive breast cancer. In xenograft-based studies, SNX27-depleted cell lines showed prolonged survival of SCID mice, suggesting a possible implication for overexpression of the sorting nexin in tumor samples.

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Section: Mt1-mmp-mediated Ecm Degradationmentioning

confidence: 99%

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

Sharma

Parveen

Shah

et al. 2019

Journal of Cell Biology

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“…The low interest for this protease is due to the fact that the overexpression of MT4-MMP was not detected in transcriptomic studies. However, analyses by immunohistochemistry showed that the protein is very abundant in the tumor compartment of human breast cancers [13,38,54]. Several hypotheses can be envisaged, such as: (1) The existence of several transcripts resulting from alternative splicing that would not be detected in the transcriptomic analyses, (2) post-transcriptional regulation via miRNAs, (3) translation control, and/or (4) epigenetic mRNA changes [73].…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

“…Indeed, MT4-MMP stimulates cell proliferation by interacting with EGFR and enhancing its activation in response to its ligands, Epidermal Growth Factor (EGF) and Tumor Growth Factor (TGF) [38]. Moreover, superimposition of EGFR and MT4-MMP has been observed in human triple-negative breast cancer (TNBC) patients [54]. Interestingly, MT4-MMP expression has been recently identified as a biomarker for TNBC patient responses to chemotherapy and to a combination of anti-EGFR drugs such as Erlotinib and Palbociclib, an inhibitor of Cyclin-dependent kinases 4 and 6, which are involved in the cell cycle [54,55].…”

Section: Cancermentioning

confidence: 99%

“…Moreover, superimposition of EGFR and MT4-MMP has been observed in human triple-negative breast cancer (TNBC) patients [54]. Interestingly, MT4-MMP expression has been recently identified as a biomarker for TNBC patient responses to chemotherapy and to a combination of anti-EGFR drugs such as Erlotinib and Palbociclib, an inhibitor of Cyclin-dependent kinases 4 and 6, which are involved in the cell cycle [54,55]. These recent data highlight the clinical relevance of using the MT4-MMP/EGFR axis to select patients who could benefit from specific combinations of targeted therapies.…”

Section: Cancermentioning

confidence: 99%

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MT4-MMP: The GPI-Anchored Membrane-Type Matrix Metalloprotease with Multiple Functions in Diseases

Yip

Foidart

Noël

et al. 2019

IJMS

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MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes, including embryogenesis, organogenesis, tissue regeneration, angiogenesis, wound healing, and inflammation. MT4-MMP (MMP17) presents unique characteristics compared to other members of the family in terms of sequence homology, substrate specificity, and internalization mode, suggesting distinct physiological and pathological functions. While the physiological functions of MT4-MMP are poorly understood, it has been involved in different pathological processes such as arthritis, cardiovascular disease, and cancer progression. The mt4-mmp transcript has been detected in a large diversity of cancers. The contribution of MT4-MMP to tumor development has been further investigated in gastric cancer, colon cancer, head and neck cancer, and more deeply in breast cancer. Given its contribution to different pathologies, particularly cancers, MT4-MMP represents an interesting therapeutic target. In this review, we examine its biological and structural properties, and we propose an overview of its physiological and pathological functions.

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“…Interestingly, this result was associated with increased cyclins and CDK activities and RB phosphorylation (12). Through IHC analysis, we previously reported that MT4-MMP is coexpressed with EGFR in approximately 80% of human TNBC samples (15). Here, we investigate the relevance of targeting EGFR and CDK4/6 in TNBCs expressing MT4-MMP, EGFR, and RB.…”

Section: Introductionmentioning

confidence: 88%

Expression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy

Foidart

Yip

Radermacher

et al. 2019

Clinical Cancer Research

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Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triplenegative breast cancer (TNBC), both in human samples and in patient-derived xenografts of TNBC (PDX-TNBC): EGFR, its recently identified partner (MT4-MMP), and retinoblastoma protein (RB).Experimental Design: IHC analyses were conducted on human and PDX-TNBC samples to evaluate the production of the three biomarkers. The sensitivity of cancer cells expressing or not MT4-MMP to anti-EGFR (erlotinib) or anti-CDK4/6 inhibitor (palbociclib) was evaluated in vitro in 2D and 3D proliferation assays and in vivo using xenografts and PDX-TNBC displaying different RB, MT4-MMP, and EGFR status after single (erlotinib or palbociclib) or combined (erlotinib þ palbociclib) treatments.Results: EGFR and MT4-MMP were coexpressed in >70% of TNBC samples and PDX-TNBC, among which approximately 60% maintained RB expression. Notably, approximately 50% of all TNBC and PDX-TNBC expressed the three biomarkers. Single erlotinib and palbociclib treatments drastically reduced the in vitro proliferation of cells expressing EGFR and MT4-MMP when compared with control cells. Both TNBC xenografts and PDX expressing MT4-MMP, EGFR, and RB, but not PDX-TNBC with RB loss, were sensitive to erlotinib and palbociclib with an additive effect of combination therapy. Moreover, this combination was efficient in another PDX-TNBC expressing the three biomarkers and resistant to erlotinib alone.Conclusions: We defined a new association of three biomarkers (MT4-MMP/EGFR/RB) expressed together in 50% of TNBC and demonstrated its usefulness to predict the TNBC response to anti-EGFR and anti-CDK4/6 drugs used in single or combined therapy.

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

Cited by 16 publications

References 38 publications

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

MT4-MMP: The GPI-Anchored Membrane-Type Matrix Metalloprotease with Multiple Functions in Diseases

Expression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy

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