Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning, Per Eystein; Knappskog, Stian

doi:10.1038/onc.2013.48

Cited by 48 publications

(44 citation statements)

References 267 publications

(263 reference statements)

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“…Among TP53 wild-type breast cancers revealing primary resistance to anthracyclines, mutations in the p53 upstream activator CHEK2 [23] or low expression levels of ATM [24] have been observed. Yet, additional factors are known to influence p53 activation in response to genotoxic stress [25, 26]. One such factor is the PTEN protein encoded by the PTEN gene [10].…”

Section: Discussionmentioning

confidence: 99%

High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function

Yndestad

Austreid

Knappskog

et al. 2017

Breast Cancer Res Treat

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PurposePTEN is an important tumor suppressor in breast cancer. Here, we examined the prognostic and predictive value of PTEN and PTEN pseudogene (PTENP1) gene expression in patients with locally advanced breast cancer given neoadjuvant chemotherapy.MethodsThe association between pretreatment PTEN and PTENP1 gene expression, response to neoadjuvant chemotherapy, and recurrence-free and disease-specific survival was assessed in 364 patients with locally advanced breast cancer given doxorubicin, 5-fluorouracil/mitomycin, or epirubicin versus paclitaxel in three phase II prospective studies. Further, protein expression of PTEN or phosphorylated Akt, S6 kinase, and 4EBP1 was assessed in a subgroup of 187 tumors.ResultsNeither PTEN nor PTENP1 gene expression level predicted response to any of the chemotherapy regimens tested (n = 317). Among patients without distant metastases (n = 282), a high pretreatment PTEN mRNA level was associated with inferior relapse-free (RFS; p = 0.001) and disease-specific survival (DSS; p = 0.003). Notably, this association was limited to patients harboring TP53 wild-type tumors (RFS; p = 0.003, DSS; p = 0.009). PTEN mRNA correlated significantly with PTENP1 mRNA levels (r s = 0.456, p < 0.0001) and PTEN protein staining (r s = 0.163, p = 0.036). However, no correlation between PTEN, phosphorylated Akt, S6 kinase or 4EBP1 protein staining, and survival was recorded. Similarly, no correlation between PTENP1 gene expression and survival outcome was observed.ConclusionHigh intratumoral PTEN gene expression was associated with poor prognosis in patients with locally advanced breast cancers harboring wild-type TP53.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-017-4160-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function

Yndestad

Austreid

Knappskog

et al. 2017

Breast Cancer Res Treat

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“…Moreover, in a study targeting chemoresistant breast cancer cells following neo-adjuvant chemotherapy, we found that some patients achieved pathological complete response (pCR; defined as no residual invasive cancer in the breast and lymph nodes), which would be expected to be associated with a more favorable prognosis than that in patients who did not achieve pCR (13). Chemoresistance involves numerous complex mechanisms, including gene pathways associated with apoptosis/senescence and DNA repair, which are often influenced by communication between host and tumor cells (14). Furthermore, EMT, anti-apoptotic mechanisms, and stemness induced by the cancer microenvironment have been shown to play important roles in chemoresistance (15).…”

Section: Introductionmentioning

confidence: 99%

Platelets surrounding primary tumor cells are related to chemoresistance

et al. 2016

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Abstract.Platelets are crucial components of the tumor microenvironment that function to promote tumor progression and metastasis. In the circulation, the interaction between tumor cells and platelets increases invasiveness, protects tumor cells from shear stress and immune surveillance, and facilitates tumor cell extravasation to distant sites. However, the role and presence of platelets in the primary tumor have not been fully determined. Here, we investigated the presence of platelets around breast cancer primary tumor cells and the associations between these cells. We further investigated the associations among platelets, tumor cells, chemoresistance, and epithelial-mesenchymal transition (EMT). We retrospectively analyzed data from 74 patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer who underwent biopsies before treatment and subsequent neo-adjuvant chemotherapy. In biopsy specimens, we evaluated the expression of platelet-specific markers and EMT markers using immunohistochemistry. The associations among the expression of platelet-specific markers in biopsy specimens, EMT, response to neo-adjuvant chemotherapy, and survival were analyzed. The presence of platelets was observed in 44 out of 74 (59%) primary breast cancer biopsy specimens. Platelet-positive tumor cells showed EMT-like morphological changes and EMT marker expression. Primary tumor cells associated with platelets were less responsive to neo-adjuvant chemotherapy (pCR rate: 10 vs. 50%, respectively; p=0.0001). Platelets were an independent predictor of the response to chemotherapy upon multivariable analysis (p<0.0001). In conclusion, there was a significant association between platelets surrounding primary tumor cells in the biopsy specimens and the chemotherapeutic response in breast cancer. Platelets surrounding primary tumor cells may represent novel predictors of chemotherapeutic responses.

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“…Chemoresistance, both intrinsic and acquired, is a main cause of recurrences or failure of current treatment 2 . Up to date, several factors contributed to the development of chemoresistance including genetic alterations 3 , altered drug accumulation 4 , drug-target amplification 5 , and autophagy 6 . Many cellular signaling pathways have been studied to explore the mechanism of chemoresistance of osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-140-5p regulates osteosarcoma chemoresistance by targeting HMGN5 and autophagy

Meng

Gao

et al. 2017

Sci Rep

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Chemotherapy is an important treatment modality for osteosarcoma. However, it often fails because of chemoresistance, especially multidrug resistance. Previously, we found several genes were involved in chemoresistance development. In this report, we used high-throughput microRNA (miRNA) expression analysis to reveal that expression of miR-140-5p was associated with chemosensitivity in osteosarcoma. The exact roles of miR-140-5p in the chemoresistance of osteosarcoma were then investigated, we found that knockdown of miR-140-5p enhanced osteosarcoma cells resistance to multiple chemotherapeutics while overexpression of miR-140-5p sensitized tumors to chemotherapy in vitro. Moreover, in vivo, knockdown of miR-140-5p also increased the osteosarcoma cells resistance to chemotherapy. Luciferase assay and Western blot analysis showed that HMGN5 was the direct target of miR-140-5p which could positively regulated autophagy. Silencing these target genes by siRNA or inhibition of autophagy sensitized osteosarcoma cells to chemotherapy. These findings suggest that a miR-140-5p/HMGN5/autophagy regulatory loop plays a critical role in chemoresistance in osteosarcoma. In conclusion, our data elucidated that miR-140-5p promoted autophagy mediated by HMGN5 and sensitized osteosarcoma cells to chemotherapy. These results suggest a potential application of miR-140-5p in overall survival, chemoresistance prognosis and treatment.

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Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Cited by 48 publications

References 267 publications

High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function

High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function

Platelets surrounding primary tumor cells are related to chemoresistance

MicroRNA-140-5p regulates osteosarcoma chemoresistance by targeting HMGN5 and autophagy

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