The role of hmga2 on parp1 activity in triple-negative breast cancer cells
| dc.contributor.author | Kalantari, Forouh | |
| dc.contributor.examiningcommittee | Ghavami, Saeid (Human Anatomy and Cell Science) Myal, Yvonne (Pathology) | en_US |
| dc.contributor.supervisor | Hombach-Klonisch, Sabine (Human Anatomy and Cell Science) | en_US |
| dc.date.accessioned | 2017-09-01T15:20:04Z | |
| dc.date.available | 2017-09-01T15:20:04Z | |
| dc.date.issued | 2017 | |
| dc.degree.discipline | Human Anatomy and Cell Science | en_US |
| dc.degree.level | Master of Science (M.Sc.) | en_US |
| dc.description.abstract | PARP inhibitors have shown promising results in combination with DNA damaging drugs and studies on the use of PARP inhibitors in combination with other treatments are ongoing for TNBC patients. The non-histone chromatin binding protein HMGA2 is expressed in embryonic stem cells and cancer cells, including triple-negative breast cancer cells (TNBC). HMGA2 enhances resistance to chemotherapeutics by enhancing base excision repair (BER) capability and decreases apoptosis by modulating the ATM and ATR DNA damage signaling pathways. Here we hypothesized that HMGA2 increases DNA damage-induced PARP1 activity and increases survival and of TNBC cells. I demonstrated that HMGA2 reduced MMS-induced DNA damage, increased cell survival and reduced apoptosis in triple-negative cancer cells. We identified PARP, an ADP-ribosylating enzyme recruited to DNA damage sites, as a novel HMGA2-interaction partner and showed that PARP1 activity was increased in the presence of HMGA2. This required functional AT hook domains of HMGA2. HMGA2 reduced the sensitivity of triple-negative breast cancer cells towards PARP1 inhibitors. Silencing of HMGA2 resulted in decreased cell survival and increased apoptosis following treatment with MMS and Olaparib. In conclusion, we identified for the first time HMGA2 as a novel regulator of PARP1 activity in cancer cells causing a reduced sensitivity towards PARP1 inhibitors. This suggests that HMGA2 may be a promising new target for combinatorial therapies in using PARP inhibitors in HMGA2-positive tumors. | en_US |
| dc.description.note | October 2017 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/32413 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Tnbc, Hmga2, Parp1, Par | en_US |
| dc.title | The role of hmga2 on parp1 activity in triple-negative breast cancer cells | en_US |
| dc.type | master thesis | en_US |