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Doctoral thesis
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English

BRCA1-deficient triple-negative breast cancer: an intertwining of ovarian hormones, DNA repair and immune response

ContributorsRomanens, Louorcid
Defense date2022-11-25
Abstract

A woman has a 13% risk of developing breast cancer in her lifetime. If she carries a germline mutation in the BRCA1 gene, this risk increases to 80%. The most frequent tumor subtype developed in BRCA1 mutation carriers is triple-negative breast cancers (TNBC), which is also the most aggressive subtype. Currently, treating TNBC is particularly challenging because of the lack of therapeutic targets; therefore, treatment options are mainly limited to chemotherapy. Nevertheless, BRCA1-deficient TNBCs display distinctive features that are of interest to establish new and targetable therapeutic strategies: they are responsive to ovarian hormones, they have defective DNA damage repair due to loss of BRCA1 function and incompetent homologous recombination, and they harbor high immune infiltrate. Despite these multiple putative angles of attack, targeted treatments are so far unsuccessful in the clinic, and BRCA1 TNBCs still have unmet medical needs. Therefore, it is important to improve our understanding of the biology of this disease. Here, we aimed to investigate the relationship between ovarian hormones, DNA repair deficiency and immune response in this disease.

The purpose of this thesis was to improve our understanding of BRCA1-deficient TNBC’s biology by studying its distinctive features and the link between them, specifically shedding light on TNBC’s immune microenvironment. The main goals of this thesis were to:

• Develop new tools of molecular pathology for studying the spatial distribution and composition of the immune infiltrate of TNBC

• Unravel the impact of menopause on the tumor immune microenvironment in BRCA1-deficient TNBC in situ

• Investigate the immune modulations induced by the combination of PARPi olaparib and anti-PD1 in a syngeneic mouse model of BRCA1-deficient TNBC

eng
Keywords
  • Breast cancer
  • Triple-negative breast cancer
  • BRCA1
  • Hormones
  • PARP inhibitors
  • Tumor microenvironment
  • Immune checkpoints
Citation (ISO format)
ROMANENS, Lou. <i>BRCA1</i>-deficient triple-negative breast cancer: an intertwining of ovarian hormones, DNA repair and immune response. 2022. doi: 10.13097/archive-ouverte/unige:165758
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Creation12/15/2022 10:04:00 AM
First validation12/15/2022 10:04:00 AM
Update time03/16/2023 10:14:20 AM
Status update03/16/2023 10:14:19 AM
Last indexation02/01/2024 9:19:06 AM
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