Targeting DNA Damage Response in Prostate and Breast Cancer
Steroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/21/8273 |
| _version_ | 1797548808959164416 |
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| author | Antje M. Wengner Arne Scholz Bernard Haendler |
| author_facet | Antje M. Wengner Arne Scholz Bernard Haendler |
| author_sort | Antje M. Wengner |
| collection | DOAJ |
| description | Steroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress at the genomic DNA level. Transcriptionally active regions are generally instable and prone to breakage due to the torsional stress and local depletion of nucleosomes that make DNA more accessible to damaging agents. A dedicated DNA damage response (DDR) is therefore essential to maintain genome integrity at these exposed regions. The DDR is a complex network involving DNA damage sensor proteins, such as the poly(ADP-ribose) polymerase 1 (PARP-1), the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the ataxia–telangiectasia-mutated (ATM) kinase and the ATM and Rad3-related (ATR) kinase, as central regulators. The tight interplay between the DDR and steroid hormone receptors has been unraveled recently. Several DNA repair factors interact with the androgen and estrogen receptors and support their transcriptional functions. Conversely, both receptors directly control the expression of agents involved in the DDR. Impaired DDR is also exploited by tumors to acquire advantageous mutations. Cancer cells often harbor germline or somatic alterations in DDR genes, and their association with disease outcome and treatment response led to intensive efforts towards identifying selective inhibitors targeting the major players in this process. The PARP-1 inhibitors are now approved for ovarian, breast, and prostate cancer with specific genomic alterations. Additional DDR-targeting agents are being evaluated in clinical studies either as single agents or in combination with treatments eliciting DNA damage (e.g., radiation therapy, including targeted radiotherapy, and chemotherapy) or addressing targets involved in maintenance of genome integrity. Recent preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented. Importantly, the combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation. |
| first_indexed | 2024-03-10T15:05:03Z |
| format | Article |
| id | doaj.art-5e32cd80f94849e6a8a16ed292cd13ee |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:05:03Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5e32cd80f94849e6a8a16ed292cd13ee2023-11-20T19:49:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012121827310.3390/ijms21218273Targeting DNA Damage Response in Prostate and Breast CancerAntje M. Wengner0Arne Scholz1Bernard Haendler2Preclinical Research, Research & Development, Pharmaceuticals, Bayer AG, Müllerstr. 178, 13353 Berlin, GermanyPreclinical Research, Research & Development, Pharmaceuticals, Bayer AG, Müllerstr. 178, 13353 Berlin, GermanyPreclinical Research, Research & Development, Pharmaceuticals, Bayer AG, Müllerstr. 178, 13353 Berlin, GermanySteroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress at the genomic DNA level. Transcriptionally active regions are generally instable and prone to breakage due to the torsional stress and local depletion of nucleosomes that make DNA more accessible to damaging agents. A dedicated DNA damage response (DDR) is therefore essential to maintain genome integrity at these exposed regions. The DDR is a complex network involving DNA damage sensor proteins, such as the poly(ADP-ribose) polymerase 1 (PARP-1), the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the ataxia–telangiectasia-mutated (ATM) kinase and the ATM and Rad3-related (ATR) kinase, as central regulators. The tight interplay between the DDR and steroid hormone receptors has been unraveled recently. Several DNA repair factors interact with the androgen and estrogen receptors and support their transcriptional functions. Conversely, both receptors directly control the expression of agents involved in the DDR. Impaired DDR is also exploited by tumors to acquire advantageous mutations. Cancer cells often harbor germline or somatic alterations in DDR genes, and their association with disease outcome and treatment response led to intensive efforts towards identifying selective inhibitors targeting the major players in this process. The PARP-1 inhibitors are now approved for ovarian, breast, and prostate cancer with specific genomic alterations. Additional DDR-targeting agents are being evaluated in clinical studies either as single agents or in combination with treatments eliciting DNA damage (e.g., radiation therapy, including targeted radiotherapy, and chemotherapy) or addressing targets involved in maintenance of genome integrity. Recent preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented. Importantly, the combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation.https://www.mdpi.com/1422-0067/21/21/8273DNA repairDNA damage responsehormone-dependentprostate cancerbreast cancerradiation |
| spellingShingle | Antje M. Wengner Arne Scholz Bernard Haendler Targeting DNA Damage Response in Prostate and Breast Cancer International Journal of Molecular Sciences DNA repair DNA damage response hormone-dependent prostate cancer breast cancer radiation |
| title | Targeting DNA Damage Response in Prostate and Breast Cancer |
| title_full | Targeting DNA Damage Response in Prostate and Breast Cancer |
| title_fullStr | Targeting DNA Damage Response in Prostate and Breast Cancer |
| title_full_unstemmed | Targeting DNA Damage Response in Prostate and Breast Cancer |
| title_short | Targeting DNA Damage Response in Prostate and Breast Cancer |
| title_sort | targeting dna damage response in prostate and breast cancer |
| topic | DNA repair DNA damage response hormone-dependent prostate cancer breast cancer radiation |
| url | https://www.mdpi.com/1422-0067/21/21/8273 |
| work_keys_str_mv | AT antjemwengner targetingdnadamageresponseinprostateandbreastcancer AT arnescholz targetingdnadamageresponseinprostateandbreastcancer AT bernardhaendler targetingdnadamageresponseinprostateandbreastcancer |