Midtveisevaluering - Anna Kristine Myrmel Sæle
Midtveisevaluering for ph.d.-graden ved Universitetet i Bergen for kandidat Anna Kristine Myrmel Sæle
Anna Kristine Myrmel Sæle er tilknyttet Klinisk institutt 1. Veiledere er Elisabeth Wik og Lars A. Akslen.
Hormone receptor regulators and immune responses in primary and metastatic breast cancer
Breast cancer (BC) is a heterogeneous disease, and despite continuous improvements in diagnostic and therapeutic handling, aggressive breast cancer remains a challenge. The project assesses the hormone receptor regulators GATA3 and FOXA1, their relations to biological processes contributing to tumor progression, immune responses, and other factors influencing the tumor microenvironment (TME). We aim to discover clinically relevant biomarkers identifying subgroups of patients aiding improved precision in the management of aggressive BC.
The transcription factor GATA3 is linked to estrogen receptor biology, and is associated with tissue differentiation and cell regulation. Previous studies have shown that loss of GATA3 associates with aggressive characteristics in several tumors, including BC. In subproject one, we used protein expression by immunohistochemistry (IHC) and global mRNA data to examine GATA3 expression in primary BC. We documented strong associations between low GATA3 and adverse clinico-pathologic characteristics, and features contributing to an aggressive TME. We discovered immune- and metabolic alterations, and novel associations to an independent value of GATA3 reflecting strong relations to immunological responses, with potential for influencing responses to immunotherapies. In mapping drug-effect gene expression profiles using cell-line exposure data, the results indicated possible relevance for adjuvant HMGCS- inhibition in GATA3-low tumors.
GATA3 is described as one of the most frequently mutated genes in BC. The role of GATA3 amplifications has however not been fully elucidated. In subproject two, we have investigated GATA3 amplifications and gene expression in global datasets of cancer genomics, and plan to conduct GATA3 FISH- analyses on BC tissue. Preliminary results indicate that GATA3 amplifications segregates with aggressive tumor characteristics, and reduced survival in subsets of BC.
In the third part of the project, we are assessing relations between GATA3, ERα and FOXA1 in protein and transcriptional data. We will examine relations between hormone receptor regulators, immune responses, and biological programs contributing to tumor progression. Data from previous studies will be integrated, along with analysis of corresponding metastatic BC lesions. Preliminary data on FOXA1 protein- and mRNA expression shows its close relations to GATA3- and ER biology. Loss of FOXA1 associates with aggressive clinico-pathologic features, increased immune responses, and reduced survival.