Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

Karlsson, Elin; Veenstra, Cynthia; Emin, Shad; Dutta, Chhanda; Pérez-Tenorio, Gizeh; Nordenskjöld, Bo; Fornander, Tommy; Stål, Olle

doi:10.1007/s10549-015-3516-y

Cited by 32 publications

(32 citation statements)

References 52 publications

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“…TAM is widely used for treating ER-positive BCs, but its side effects and the gradual development of insensitivity limit its effectiveness. Many studies have shown that resistance to TAM is partly mediated through the AKT pathway, which promotes estrogen-independent cell proliferation [ 20 ]. The AKT pathway also plays a crucial role in breast cancer pathogenesis, and AKT upregulation is associated with more aggressive clinical phenotypes and worse outcomes in endocrine-treated patients [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Huaier extract synergizes with tamoxifen to induce autophagy and apoptosis in ER-positive breast cancer cells

Sun

Kong

et al. 2016

Oncotarget

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Tamoxifen (TAM) is the most widely used endocrine therapy for estrogen receptor (ER)-positive breast cancer patients, but side effects and the gradual development of insensitivity limit its application. We investigated whether Huaier extract, a traditional Chinese medicine, in combination with TAM would improve treatment efficacy in ER-positive breast cancers. MTT, colony formation, and invasion and migration assays revealed that the combined treatment had stronger anticancer effects than either treatment alone. Huaier extract enhanced TAM-induced autophagy, apoptosis, and G0/G1 cell cycle arrest, as measured by acidic vesicular organelle (AVO) staining, TUNEL, flow cytometry, and western blot. Additionally, combined treatment inhibited tumorigenesis and metastasis by suppressing the AKT/mTOR signaling pathway. Huaier extract also enhanced the inhibitory effects of TAM on tumor growth in vivo in a xenograft mouse model. These results show that Huaier extract synergizes with TAM to induce autophagy and apoptosis in ER-positive breast cancer cells by suppressing the AKT/mTOR pathway.

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Section: Discussionmentioning

confidence: 99%

Huaier extract synergizes with tamoxifen to induce autophagy and apoptosis in ER-positive breast cancer cells

Sun

Kong

et al. 2016

Oncotarget

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“…Targeted therapies, such as tamoxifen and trastuzumab, have improved the outcomes of patients with ER + or HER2 + breast cancer (3,4). However, a number of patients with breast cancer exhibit de novo or acquired target therapy resistance (5,6). In addition, chemotherapy is the only treatment option for patients with triple-negative breast cancer (TNBC; ER -/HER2 -/PR -) and targets for the effective treatment remain to be elucidated (7).…”

Section: Introductionmentioning

confidence: 99%

miR‑532‑5p promotes breast cancer proliferation and migration by targeting RERG

et al. 2019

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Aberrant expression of microRNAs (miRNAs/miRs) mediates the initiation and progression of breast cancer. Therefore, it is important to investigate the molecular mechanisms of miRNAs and their effects on breast cancer progression. In the present study, miR-532-5p was highly expressed in breast cancer tissues compared with normal tissues. In addition, expression of ras-related and estrogen-regulated growth inhibitor (RERG), a tumor suppressor in breast cancer, was negatively correlated with miR-532-5p expression. Inhibition of miR-532-5p significantly elevated RERG at both mRNA and protein levels and inactivated the mitogen-activated protein kinase (MAPK)/ERK signaling pathway. Overexpression of miR-532-5p decreased RERG expression and activated the MAPK/ERK signaling in breast cancer cell line MDA-MB-231. Bioinformatic analysis indicated that RERG 3'-untraslated region contained a putative binding site for miR-532-5p. Dual luciferase assay further validated RERG as a target gene of miR-532-5p. Notably, downregulation of miR-532-5p inhibited MDA-MB-231 cell proliferation and migration, which was partially attenuated upon RERG knockdown. In conclusion, the current study revealed an oncogenic role of miR-532-5p in breast cancer cells via direct targeting of RERG expression.

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“…Activation of the phosphatidyl-inositol-3 kinase pathway as measured by phosphorylation status of components of the protein cascade has been shown to correlate with tamoxifen resistance, while this was not found for its upstream drivers like the presence of a PIK3CA hotspot mutation, or PTEN loss [ 29 , 30 ]. AKT inhibitors have been shown to extend the duration of response to both tamoxifen and AI in pre-clinical models [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Dissecting the predictive value of MAPK/AKT/estrogen-receptor phosphorylation axis in primary breast cancer to treatment response for tamoxifen over exemestane: a Translational Report of the Intergroup Exemestane Study (IES)—PathIES

Szíjgyártó

Flach

Opdam

et al. 2019

Breast Cancer Res Treat

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Purpose The prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2–3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES). Methods Of the 4724 patients in IES, 1506 were managed in a subset of centres ( N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini–Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied ( p BH ). Results Phospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated ( p BH = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant ( p BH > 0.05 for all). Conclusions This PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone. Electronic supplementary material The online version of this article (10.1007/s10549-018-05110-x) contains supplementary material, which is available to authorized users.

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Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

Cited by 32 publications

References 52 publications

Huaier extract synergizes with tamoxifen to induce autophagy and apoptosis in ER-positive breast cancer cells

Huaier extract synergizes with tamoxifen to induce autophagy and apoptosis in ER-positive breast cancer cells

miR‑532‑5p promotes breast cancer proliferation and migration by targeting RERG

Dissecting the predictive value of MAPK/AKT/estrogen-receptor phosphorylation axis in primary breast cancer to treatment response for tamoxifen over exemestane: a Translational Report of the Intergroup Exemestane Study (IES)—PathIES

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