Metalloprotease-disintegrin ADAM12 actively promotes the stem cell-like phenotype in claudin-low breast cancer

Duhachek-Muggy, Sara; Qi, Yue; Wise, Randi; Alyahya, Linda; Li, Hui; Hodge, Jacob; Żółkiewska, Anna

doi:10.1186/s12943-017-0599-6

Cited by 44 publications

(38 citation statements)

References 71 publications

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“…Partial activation of EGFR in SUM159PT and SUM149PT cells in the absence of the exogenously added EGF, which was also observed previously in our lab in SUM159PT cells in serum-free media [37], suggested that EGFR might have been activated by endogenously expressed ligands. All EGFR ligands are synthesized as transmembrane precursors that need to be converted to biologically active, soluble molecules via cleavage by ADAM metalloproteases [26, 27].…”

Section: Resultssupporting

confidence: 83%

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Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

Wise

Żółkiewska

2017

Breast Cancer Res Treat

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Purpose The CD44+/CD24− cell phenotype is enriched in triple negative breast cancers (TNBCs), is associated with tumor invasive properties, and serves as a cell surface marker profile of breast cancer stem-like cells. Activation of Epidermal Growth Factor Receptor (EGFR) promotes the CD44+/CD24− phenotype, but the specific signaling pathway downstream of EGFR responsible for this effect is not clear. The purpose of this study was to determine the role of the MEK/ERK pathway in the expansion of CD44+/CD24− populations in TNBC cells in response to EGFR activation. Methods Representative TNBC cell lines SUM159PT (claudin-low) and SUM149PT (basal) were used to evaluate cell surface expression of CD44 and CD24 by flow cytometry in response to EGFR and MEK inhibition or activation. EGFR and ERK phosphorylation levels were analyzed by Western blotting. The relationship between EGFR phosphorylation and MEK activation score in basal and claudin-low tumors from the TCGA database was examined. Results Inhibition of ERK activation with selumetinib, a MEK1/2 inhibitor, blocked EGF-induced expansion of CD44+/CD24− populations. Sustained activation of ERK by overexpression of constitutively active MEK1 was sufficient to expand CD44+/CD24− populations in cells in which EGFR activity was blocked by either erlotinib, an EGFR kinase inhibitor, or BB-94, a metalloprotease inhibitor that prevents generation of soluble EGFR ligands. In basal and claudin-low tumors from the TCGA database, there was a positive correlation between EGFR_pY1068 and MEK activation score in tumors without genomic loss of DUSP4, a negative regulator of ERK, but not in tumors harboring DUSP4 deletion. Conclusion Our results demonstrate that ERK activation is a key event in EGFR-dependent regulation of CD44+/CD24− populations. Furthermore, our findings highlight the role of ligand-mediated EGFR signaling in the control of MEK/ERK pathway output in TNBC tumors without DUSP4 loss.

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Section: Resultssupporting

confidence: 83%

“…Cell culture, retroviral transduction, generation of stable cell lines , and immunoblotting were performed as previously described [35–37]. Additional experimental details are provided in Online Resource 1: Supplementary Methods.…”

Section: Methodsmentioning

confidence: 99%

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

Wise

Żółkiewska

2017

Breast Cancer Res Treat

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“…It belongs to a matrix metalloproteinase-related protein family and participates in the proteolytic processing of other transmembrane proteins, with consequences for cell-signalling events, transcription, RNA metabolism, apoptosis, cell-cycle progression, and cell adhesion. ADAM12 overexpression has been reported in many tumours [31,32], especially in BC, where it has been proposed to make an important contribution in carcinogenesis [33][34][35][36]. However, its molecular status in the TNBC subtype is almost entirely unexplored.…”

Section: Discussionmentioning

confidence: 99%

ADAM12 is A Potential Therapeutic Target Regulated by Hypomethylation in Triple-Negative Breast Cancer

Mendaza

Ulazia-Garmendia

Monreal-Santesteban

et al. 2020

IJMS

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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and currently lacks any effective targeted therapy. Since epigenetic alterations are a common event in TNBC, DNA methylation profiling can be useful for identifying potential biomarkers and therapeutic targets. Here, genome-wide DNA methylation from eight TNBC and six non-neoplastic tissues was analysed using Illumina Human Methylation 450K BeadChip. Results were validated by pyrosequencing in an independent cohort of 50 TNBC and 24 non-neoplastic samples, where protein expression was also assessed by immunohistochemistry. The functional role of disintegrin and metalloproteinase domain-containing protein 12(ADAM12) in TNBC cell proliferation, migration and drug response was analysed by gene expression silencing with short hairpin RNA. Three genes (Von Willenbrand factor C and Epidermal Growth Factor domain-containing protein (VWCE), tetraspanin-9 (TSPAN9) and ADAM12) were found to be exclusively hypomethylated in TNBC. Furthermore, ADAM12 hypomethylation was associated with a worse outcome in TNBC tissues and was also found in adjacent-to-tumour tissue and, preliminarily, in plasma from TNBC patients. In addition, ADAM12 silencing decreased TNBC cell proliferation and migration and improved doxorubicin sensitivity in TNBC cells. Our results indicate that ADAM12 is a potential therapeutic target and its hypomethylation could be a poor outcome biomarker in TNBC.

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“…Indeed, recently, it has been reported that ADAM12 was elevated in claudin-low tumor and a part of stromal, mammosphere, and EMT gene signatures, which were all associated with breast tumor-initiating cells (BTICs). Thus, ADAM12 may serve as a novel marker and/or a novel therapeutic target in BTICs 27 , 37 . However, the correlation between drug-induced chemoresistance and the expression of potential drug target molecule (along with the related mechanisms) such as ADAM12 has yet to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

ADAM12-L confers acquired 5-fluorouracil resistance in breast cancer cells

Wang

et al. 2017

Sci Rep

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5-FU-based combinatory chemotherapeutic regimens have been routinely used for many years for the treatment of breast cancer patients. Recurrence and chemotherapeutic drug resistance are two of the most prominent factors that underpin the high mortality rates associated with most breast cancers (BC). Increasing evidence indicates that overexpression of ADAMs could correlate with cancer progression. However, the role of ADAMs in the chemoresistance of cancer cells has rarely been reported. In this study, we observed that 5-FU induces expression of the ADAM12 isoform ADAM12-L but not ADAM12-S in BC cells and in recurrent BC tissues. The overexpression of ADAM12-L in BC cells following 5-FU treatment results in the acquisition of resistance to 5-FU. ADAM12-L overexoression also resulted in increased levels of p-Akt but not p-ERK. These alterations enhanced BC cell growth and invasive abilities. Conversely, ADAM12 knockdown attenuated the levels of p-Akt and restored 5-FU sensitivity in 5-FU-resistant BC cells. ADAM12 knockdown also reduced BC cell survival and invasive abilities. These findings suggest that ADAM12-L mediates chemoresistance to 5-FU and 5-FU-induced recurrence of BC by enhancing PI3K/Akt signaling. The results of this study suggest that specific ADAM12-L inhibition could optimize 5-FU-based chemotherapy of BC, thereby preventing BC recurrence in patients.

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Metalloprotease-disintegrin ADAM12 actively promotes the stem cell-like phenotype in claudin-low breast cancer

Cited by 44 publications

References 71 publications

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

ADAM12 is A Potential Therapeutic Target Regulated by Hypomethylation in Triple-Negative Breast Cancer

ADAM12-L confers acquired 5-fluorouracil resistance in breast cancer cells

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