Identification of an AKT-dependent signalling pathway that mediates tamoxifen-dependent induction of the pro-metastatic protein anterior gradient-2

Hrstka, Roman; Murray, Euan; Brychtová, Veronika; Fabián, Pavel; Hupp, Ted R.; Vojtěšek, Bořivoj

doi:10.1016/j.canlet.2013.01.034

Cited by 23 publications

(15 citation statements)

References 26 publications

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“…However, we are as yet unable to reconcile these findings with those of others in the same cell line, which indicates that the induction of AGR2 gene expression in response to tamoxifen occurs as a result of the non-genomic activity of ERα on signaling molecules in an AKT dependent manner (30). This encouraged us to undertake a comparative bioinformatics analysis to define proteins and/or processes that may be involved in AGR2 expression in this context.…”

Section: Discussioncontrasting

confidence: 70%

Delineation of a FOXA1/ERα/AGR2 Regulatory Loop That Is Dysregulated in Endocrine Therapy–Resistant Breast Cancer

Wright

Wardell

Jasper

et al. 2014

Molecular Cancer Research

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Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), remains a frontline clinical therapy for patients with ERα-positive breast cancer. However, the relatively rapid development of resistance to this drug in the metastatic setting remains an impediment to a durable response. Although drug resistance likely arises by many different mechanisms, the consensus is that most of the implicated pathways facilitate the outgrowth of a subpopulation of cancer cells that can either recognize tamoxifen as an agonist or bypass the regulatory control of ERα. Notable in this regard is the observation here and in other studies that expression of anterior gradient homology 2 (AGR2), a known proto-oncogene and disulfide isomerase, was induced by both estrogen (17β-estradiol, E2) and 4-hydroxytamoxifen (4OHT) in breast cancer cells. The importance of AGR2 expression is highlighted here by the observation that (a) its knockdown inhibited the growth of both tamoxifen-sensitive and -resistant breast cancer cells, and (b) its increased expression enhanced the growth of ERα-positive tumors in vivo and increased the migratory capacity of breast cancer cells in vitro. Interestingly, as with most ERα-target genes, the expression of AGR2 in all breast cancer cells examined requires the transcription factor FOXA1. However, in tamoxifen-resistant cells, the expression of AGR2 occurs in a constitutive manner, requiring FOXA1, but loses its dependence on ER. Taken together, these data define the importance of AGR2 in breast cancer cell growth and highlights a mechanism where changes in FOXA1 activity obviate the need for ER in the regulation of this gene.

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Section: Discussioncontrasting

confidence: 70%

Delineation of a FOXA1/ERα/AGR2 Regulatory Loop That Is Dysregulated in Endocrine Therapy–Resistant Breast Cancer

Wright

Wardell

Jasper

et al. 2014

Molecular Cancer Research

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“…The clinical relevance of ER crosstalk with growth factor signaling pathways was confirmed by prospective trials in patients with metastatic disease, showing that tamoxifen resistance is associated with high expression of receptor tyrosine kinases HER2 and EGFR [14]. Interestingly, recent reports indicate that AGR2 is involved in the crosstalk between ER and EGFR [15] or PI3K/AKT [16] resulting in endocrine resistance, providing a potential mechanistic basis for our observations.…”

Section: Discussionsupporting

confidence: 58%

AGR2 Predicts Tamoxifen Resistance in Postmenopausal Breast Cancer Patients

et al. 2013

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Endocrine resistance is a significant problem in breast cancer treatment. Thus identification and validation of novel resistance determinants is important to improve treatment efficacy and patient outcome. In our work, AGR2 expression was determined by qRT-PCR in Tru-Cut needle biopsies from tamoxifen-treated postmenopausal breast cancer patients. Our results showed inversed association of AGR2 mRNA levels with primary treatment response (P = 0.0011) and progression-free survival (P = 0.0366) in 61 ER-positive breast carcinomas. As shown by our experimental and clinical evaluations, elevated AGR2 expression predicts decreased efficacy of tamoxifen treatment. From this perspective, AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in postmenopausal ER-positive breast cancer patients.

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“…Moreover, AGR2 expression is suppressed by SMAD4 that is a tumor suppressor of pancreatic ductal adenocarcinoma [30]. In addition, induction of AGR2 expression by tamoxifen through AKT or Src has been implicated in tamoxifen resistance of breast cancer cells [31]. Both AGR2-mediated inhibition of p53 tumor suppressor activity and AGR2-associated expression of genes that regulate cell growth and survival may directly contribute to the tumor-promoting activity of AGR2 through augmented cell proliferation and survival.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of anterior gradient 2 expression extenuates tumor-associated phenotypes of SNU-478 ampulla of Vater cancer cells

et al. 2014

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BackgroundAnterior gradient 2 (AGR2) has been implicated in tumor-associated phenotypes such as cell viability, invasion and metastasis in various human cancers. However, the tumor promoting activity of AGR2 has not yet been determined in biliary tract cancers. Thus, we examined the expression of AGR2 and its tumor-promoting activity in biliary tract cancer cells in this study.MethodsExpression of AGR2 mRNA and protein was analyzed by real time RT-PCR and western blotting, respectively. MTT assay was employed to measure cell viability and pulsed BrdU incorporation by proliferating cells was monitored by flow cytometry. Soft agar colony formation assay and transwell invasion assay were employed to determine anchorage-independent growth and in vitro invasion of the tumor cells, respectively. In vivo tumor formation was examined by injection of tumor cells into immunocompromised mice subcutaneously. Statistical analysis was performed with 2-tailed unpaired Student’s t-test for continuous data and with one-way ANOVA for multiple group comparisons. Bonferroni tests were used for post hoc 2-sample comparisons.ResultsAGR2 mRNA was detected in SNU-245, SNU-478, and SNU-1196 cell lines, and its protein expression was confirmed in SNU-478 and SNU-245 cell lines by western blot analysis. Knockdown of AGR2 expression with an AGR2-specific short hairpin RNA (shRNA) in SNU-478, an ampulla of Vater cancer cell line resulted in decreased cell viability and in decreased anchorage-independent growth by 98%. The AGR2 knockdown also increased the sensitivity of the cells to chemotherapeutic drugs, including gemcitabine, 5-fluorouracil and cisplatin. In addition, SNU-478 cells expressing AGR2-shRNA failed to form detectable tumor xenografts in nude mice, whereas control cells formed tumors with an average size of 179 ± 84 mm3 in 3 weeks. Overexpression of AGR2 in SNU-869 cells significantly increased cell viability through enhanced cell proliferation and the number of Matrigel™-invading cells compared with AGR2-negative SNU-869 cells.ConclusionsOur findings implicate that AGR2 expression augments tumor-associated phenotypes by increasing proliferative and invasive capacities of the ampulla of Vater cancer cells.

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Identification of an AKT-dependent signalling pathway that mediates tamoxifen-dependent induction of the pro-metastatic protein anterior gradient-2

Cited by 23 publications

References 26 publications

Delineation of a FOXA1/ERα/AGR2 Regulatory Loop That Is Dysregulated in Endocrine Therapy–Resistant Breast Cancer

Delineation of a FOXA1/ERα/AGR2 Regulatory Loop That Is Dysregulated in Endocrine Therapy–Resistant Breast Cancer

AGR2 Predicts Tamoxifen Resistance in Postmenopausal Breast Cancer Patients

Knockdown of anterior gradient 2 expression extenuates tumor-associated phenotypes of SNU-478 ampulla of Vater cancer cells

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