Perspectives on Epidermal Growth Factor Receptor Regulation in Triple-Negative Breast Cancer

Williams, Christina J.; Soloff, Adam C.; Ethier, Stephen P.; Yeh, Elizabeth S.

doi:10.1016/bs.acr.2015.04.008

Cited by 24 publications

(8 citation statements)

References 121 publications

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“…Numerous reports showed that overexpression of EGFR decreased OS and DFS in women with early breast cancer [35, 36]. Therefore, it also seemed to be a major driving factor of malignancy in breast cancer [37–39]. Experiments were carried out to study whether AJAP1 had the same effect on EGFR in vivo.…”

Section: Resultsmentioning

confidence: 99%

β-Catenin nuclear localization positively feeds back on EGF/EGFR-attenuated AJAP1 expression in breast cancer

Liu

Xiang

et al. 2019

J Exp Clin Cancer Res

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Background Adherent junction associated protein 1 (AJAP1), a typical molecule of adherent junctions, has been found to be a tumor suppressor in many cancer types. Aberrant activation of β-catenin has been demonstrated to be associated with malignant biological properties of tumors including breast cancer. This study aimed to investigate the function and mechanism of AJAP1-mediated β-catenin activity of breast cancer lines in vitro and in breast cancer patients. Methods AJAP1 and β-catenin expressions in breast cancer tissues and cell lines were detected by immunohistochemistry, western blotting and qRT-PCR. The EGF/EGFR axis-mediated AJAP1 attenuated β-catenin nuclear location was measured by western blotting, immunofluorescence assay, co-immunoprecipitation, luciferase assay and ubiquitination assays. Furthermore, the function of AJAP1 and β-catenin regulated breast cancer progression was explored both in vivo and in vitro . Results It was found that AJAP1 had a high negative correlation with β-catenin nuclear expression and was a novel tumor suppressor in breast cancer. AJAP1 loss can mediate β-catenin accumulated in cytoplasm and then transferred it to the nucleus, activating β-catenin transcriptional activity and downstream genes. Additionally, β-catenin can reverse the invasion, proliferation ability and tumorigenicity of the depletion of AJAP1 caused both in vivo and in vitro. Besides, EGF/EGFR also involved in the process of AJAP1-depiction induced β-catenin transactivation to the nucleus. More importantly, EGFR depletion/AJAP1 knocked down promoted the progression of breast cancer by regulating the activity of β-catenin nuclear transactivation. Conclusion This study demonstrated that AJAP1 acted as a putative tumor suppressor while β-catenin nuclear localization positively fed back on EGF/EGFR-attenuated AJAP1 expression in breast cancer, which might be beneficial to develop new therapeutic targets for decreasing nuclear β-catenin-mediated malignancy in breast cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1252-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

β-Catenin nuclear localization positively feeds back on EGF/EGFR-attenuated AJAP1 expression in breast cancer

Liu

Xiang

et al. 2019

J Exp Clin Cancer Res

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“…Two completed clinical trials investigated the therapeutic potential of cetuximab, as a single agent or in addition to cisplatin chemotherapy, in unselected TNBC patients with metastatic disease [ 66 , 67 ]. While the results have been disappointing and there was no significant effect on progression-free or overall patient survival, it is becoming clear that EGFR expression alone does not necessarily indicate tumor cell dependence on EGFR signaling and further molecular stratifications and patient selections are needed in future trials [ 63 , 68 , 69 ]. We propose that ADAM12 may be an important biomarker in identifying TNBCs with over-activation of the EGFR pathway and may help select patients that would better respond to EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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

Duhachek-Muggy

Wise

et al. 2017

Mol Cancer

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BackgroundADAM12 is upregulated in human breast cancers and is a predictor of chemoresistance in estrogen receptor-negative tumors. ADAM12 is induced during epithelial-to-mesenchymal transition, a feature associated with claudin-low breast tumors, which are enriched in cancer stem cell (CSC) markers. It is currently unknown whether ADAM12 plays an active role in promoting the CSC phenotype in breast cancer cells.MethodsADAM12 expression was downregulated in representative claudin-low breast cancer cell lines, SUM159PT and Hs578T, using siRNA transfection or inducible shRNA expression. Cell characteristics commonly associated with the CSC phenotype in vitro (cell migration, invasion, anoikis resistance, mammosphere formation, ALDH activity, and expression of the CD44 and CD24 cell surface markers) and in vivo (tumor formation in mice using limiting dilution transplantation assays) were evaluated. RNA sequencing was performed to identify global gene expression changes after ADAM12 knockdown.ResultsWe found that sorted SUM159PT cell populations with high ADAM12 levels had elevated expression of CSC markers and an increased ability to form mammospheres. ADAM12 knockdown reduced cell migration and invasion, decreased anoikis resistance, and compromised mammosphere formation. ADAM12 knockdown also diminished ALDEFLUOR+ and CD44hi/CD24-/lo CSC-enriched populations in vitro and reduced tumorigenesis in mice in vivo. RNA sequencing identified a significant overlap between ADAM12- and Epidermal Growth Factor Receptor (EGFR)-regulated genes. Consequently, ADAM12 knockdown lowered the basal activation level of EGFR, and this effect was abolished by batimastat, a metalloproteinase inhibitor. Furthermore, incubation of cells with exogenously added EGF prevented the downregulation of CD44hi/CD24-/lo cell population by ADAM12 knockdown.ConclusionsThese results indicate that ADAM12 actively supports the CSC phenotype in claudin-low breast cancer cells via modulation of the EGFR pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0599-6) contains supplementary material, which is available to authorized users.

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“…One of the reasons is the lack of specific markers predicting which patients are most likely to respond to anti-EGFR therapies [1, 2, 52–55]. Recent studies demonstrating that EGFR inhibitors reduce CSC populations in TNBC tumors [19] further highlight the importance of EGFR in the pathology of triple-negative disease and underscore the need for better markers guiding patient selection for anti-EGFR therapies.…”

Section: Discussionmentioning

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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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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Perspectives on Epidermal Growth Factor Receptor Regulation in Triple-Negative Breast Cancer

Cited by 24 publications

References 121 publications

β-Catenin nuclear localization positively feeds back on EGF/EGFR-attenuated AJAP1 expression in breast cancer

β-Catenin nuclear localization positively feeds back on EGF/EGFR-attenuated AJAP1 expression in breast cancer

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

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

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