The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene

Tormo, Eduardo; Adam‐Artigues, Anna; Ballester, Sandra; Pineda, Begoña; Zazo, Sandra; Gónzález-Alonso, Paula; Albanell, Joan; Rovira, Ana; Rojo, Federico; Lluch, Aña; Eroles, Pîlar

doi:10.1038/srep41309

Cited by 65 publications

(52 citation statements)

References 26 publications

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“…1d ) whereas HCC1954 cells were resistant (Fig. 1c ) to trastuzumab treatment in vitro , which are in agreement with published studies by other group 30 , 31 . However, trastuzumab was quite effective in inhibiting the growth of HCC1954 tumor in our xenograft model (Fig.…”

Section: Discussionsupporting

confidence: 92%

Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer

Xiong

et al. 2017

Sci Rep

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Androgen receptor (AR) is widely expressed in different subtypes of breast cancer (BC). However, it is unclear how AR functions in HER2 positive (+) BC. Knockdown of AR with shRNAs and a new generation anti-androgen drug, Enzalutamide, were used to explore the involvement of AR on the growth of HER2 + BC cells (HCC1954 and SKBR3). AR shRNA or Enzalutamide inhibited the growth of SKBR3 cells at a similar extend compared to trastuzumab, an approved HER2 targeted drug. Combining Enzalutamide with trastuzumab further decreased the growth of HCC1954 and SKBR3 cells compared with single agent alone in vitro. Biochemical analysis revealed that inhibiting AR resulted in decreased HER2 phosphorylation and activation of Erk and Akt, without affecting the HER2 and HER3 expression. The in vivo efficacy of Enzalutamide was further tested using the HCC1954 xenograft model. Enzalutamide impaired the growth of HCC1954 tumor at a level comparable to that by trastuzumab. Enzalutamide decreased Ki67 staining and increased activated caspase3 staining compared with vehicle control in HCC1954 tumors. Our results indicate AR plays an important role in promoting the growth of HER2 + BC by cross-talking with the HER2 signaling. AR drug may be used as an alternative second line therapy for treating HER2 + BC.

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Section: Discussionsupporting

confidence: 92%

Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer

Xiong

et al. 2017

Sci Rep

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“…An overexpression of CDK2 and a high-percentile expression of CCNE2 were observed in the recurrence sample's transcriptomic analysis. These have been suggested as potential resistance markers for trastuzumab ( Scaltriti et al 2011 ; Ichikawa et al 2012 ; Tormo et al 2017 ), and we can speculate on their potential role in rendering the treatment ineffective.…”

Section: Discussionmentioning

confidence: 92%

Detection and genomic characterization of a mammary-like adenocarcinoma

Grewal

Eirew

Jones

et al. 2017

Cold Spring Harb Mol Case Stud

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Whole-genome and transcriptome sequencing were performed to identify potential therapeutic strategies in the absence of viable treatment options for a patient initially diagnosed with vulvar adenocarcinoma. Genomic events were prioritized by comparison against variant distributions in the TCGA pan-cancer data set and complemented with detailed transcriptome sequencing and copy-number analysis. These findings were considered against published scientific literature in order to evaluate the functional effects of potentially relevant genomic events. Analysis of the transcriptome against a background of 27 TCGA cancer types led to reclassification of the tumor as a primary HER2+ mammary-like adenocarcinoma of the vulva. This revised diagnosis was subsequently confirmed by follow-up immunohistochemistry for a mammary-like adenocarcinoma. The patient was treated with chemotherapy and targeted therapies for HER2+ breast cancer. The detailed pathology and genomic findings of this case are presented herein.

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“…Other CDK-cyclin complexes have been previously reported as implicated in resistance to anti-HER2 therapies. For instance, cyclin E has a role in trastuzumab resistance and treatment with CDK2 inhibitors has been proposed for tumors displaying cyclin E amplification/overexpression (26,27). A relationship of CDK4/ cyclin D1 activity in resistance to trastuzumab and lapatinib has been also reported and high levels of cyclin D1 predicted poor response to trastuzumab (28).…”

Section: Bmentioning

confidence: 99%

Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer

Sabbaghi

Gil‐Gómez

Guardia

et al. 2017

Clinical Cancer Research

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Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance. HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human-positive breast cancer explants. We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells. knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation. Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer. .

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The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene

Cited by 65 publications

References 26 publications

Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer

Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer

Detection and genomic characterization of a mammary-like adenocarcinoma

Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer

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