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Estrogen receptor beta enhances chemotherapy response of GBM cells by down regulating DNA damage response pathways.

ABSTRACT: Glioblastoma (GBM) is the most commonly diagnosed brain tumor that exhibit high mortality rate and chemotherapy resistance is a major clinical problem. Recent studies suggest that estrogen receptor beta (ER?), may function as a tumor suppressor in GBM. However, the mechanism(s) by which ER? contributes to GBM suppression and chemotherapy response remains unknown. We examined the role of ER? in the DNA damage response of GBM cells, and tested whether ER? sensitizes GBM cells to chemotherapy. Cell viability and survival assays using multiple epitope tagged ER? expressing established and primary GBM cells demonstrated that ER? sensitizes GBM cells to DNA damaging agents including temozolomide (TMZ). RNA-seq studies using ER? overexpression models revealed downregulation of number of genes involved in DNA recombination and repair, ATM signaling and cell cycle check point control. Gene set enrichment analysis (GSEA) suggested that ER?-modulated genes were correlated negatively with homologous recombination, mismatch repair and G2M checkpoint genes. Further, RT-qPCR analysis revealed that chemotherapy induced activation of cell cycle arrest and apoptosis genes were attenuated in ER?KO cells. Additionally, ER? overexpressing cells had a higher number of ?H2AX foci following TMZ treatment. Mechanistic studies showed that ER? plays an important role in homologous recombination (HR) mediated repair and ER? reduced expression and activation of ATM upon DNA damage. More importantly, GBM cells expressing ER? had increased survival when compared to control GBM cells in orthotopic GBM models. ER? overexpression further enhanced the survival of mice to TMZ therapy in both TMZ sensitive and TMZ resistant GBM models. Additionally, IHC analysis revealed that ER? tumors had increased expression of ?H2AX and cleaved caspase-3. Using ER?-overexpression and ER?-KO GBM model cells, we have provided the evidence that ER? is required for optimal chemotherapy induced DNA damage response and apoptosis in GBM cells.

SUBMITTER: Zhou M

PROVIDER: S-EPMC6467924 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Estrogen receptor beta enhances chemotherapy response of GBM cells by down regulating DNA damage response pathways.

Zhou Mei M Sareddy Gangadhara R GR Li Mengxing M Liu Jinyou J Luo Yiliao Y Venkata Prabhakar Pitta PP Viswanadhapalli Suryavathi S Tekmal Rajeshwar R RR Brenner Andrew A Vadlamudi Ratna K RK

Scientific reports 20190416 1

Glioblastoma (GBM) is the most commonly diagnosed brain tumor that exhibit high mortality rate and chemotherapy resistance is a major clinical problem. Recent studies suggest that estrogen receptor beta (ERβ), may function as a tumor suppressor in GBM. However, the mechanism(s) by which ERβ contributes to GBM suppression and chemotherapy response remains unknown. We examined the role of ERβ in the DNA damage response of GBM cells, and tested whether ERβ sensitizes GBM cells to chemotherapy. Cell ...[more]

PMID: 30992459

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Project description:Simple Summary Several chemotherapy drugs are approved for ovarian cancer treatment in the neo-adjuvant/adjuvant setting as well as following relapse. These include carboplatin, paclitaxel, doxorubicin, topotecan, PARP inhibitors (PARPi), and gemcitabine. However, except for PAPRi, there are no predictive biomarkers to guide the choice of drug. The majority of chemotherapeutic drugs function by inducing DNA damage or inhibiting its repair. However, the association of DNA damage repair (DDR) pathway alterations with therapy response remain unclear. In this study, using a panel of 14 ovarian cancer cell lines, 10 patient ascites-derived primary cultures and bioinformatic analysis of The Cancer Genome Atlas (TCGA) ovarian cancer dataset, we identified the role of genomic/transcriptomic and/or functional alterations in DDR pathways as determinants of therapy response. Abstract Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g., due to BRCA1/2 loss, is a determinant of response to platinum agents and PARP inhibitors in ovarian cancers. Most chemotherapies function by either inducing DNA damage or impacting on its repair but are generally used in the clinic unselectively. The significance of HRR and other DDR pathways in determining response to several other chemotherapy drugs is not well understood. In this study, the genomic, transcriptomic and functional analysis of DDR pathways in a panel of 14 ovarian cancer cell lines identified that defects in DDR pathways could determine response to several chemotherapy drugs. Carboplatin, rucaparib, and topotecan sensitivity were associated with functional loss of HRR (validated in 10 patient-derived primary cultures) and mismatch repair. Two DDR gene expression clusters correlating with treatment response were identified, with PARP10 identified as a novel marker of platinum response, which was confirmed in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Reduced non-homologous end-joining function correlated with increased sensitivity to doxorubicin, while cells with high intrinsic oxidative stress showed sensitivity to gemcitabine. In this era of personalised medicine, molecular/functional characterisation of DDR pathways could guide chemotherapy choices in the clinic allowing specific targeting of ovarian cancers.

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Estrogen receptor beta enhances chemotherapy response of GBM cells by down regulating DNA damage response pathways.

Publications

Estrogen receptor beta enhances chemotherapy response of GBM cells by down regulating DNA damage response pathways.

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