Midtveisevaluering - Synnøve Yndestad
The role of PTEN, PTEN pseudogene and PI3K signaling in chemotherapy resistance in human breast cancer.
For patients with metastatic breast cancer, acquired drug resistance is still an immense problem today, and new therapeutic options are required.
PI3K-Akt-mTOR (in short PI3K) signaling is frequently deregulated in breast cancer, and more than 70% of breast cancers harbors mutations in the PI3K pathway. Activation of the PI3K pathway is associated with resistance to HER2 targeted therapy, as well as endocrine treatment. While the tumor suppressor PTEN inhibits PI3K signaling, loss of PTEN function is associated with chemotherapy resistance. At the same time loss of PTEN function sensitizes cancer cells to the mTOR inhibitor everolimus. This project focuses on the role of PI3K signaling in locally advanced breast cancer and its implications for chemotherapy resistance.
The PTEN pseudogene (PTENP1) has 98% sequence homology with PTEN mRNA, and functions as a long non-coding RNA which adsorb microRNAs targeted to degrade PTEN, thus protecting PTEN from degradation in prostate cancer. PTEN expression is often repressed in breast cancer, but the mechanism behind is not fully understood. Since PTENP1 influenced PTEN expression in prostate cancer, we wanted to assess how PTENP1 affects growth and PI3K signaling in breast cancer, and examine whether deregulation of the pseudogene affects response to therapy.
We examined PI3K signaling in biopsies taken from patients with locally advanced breast cancer in four different patient cohorts and correlated immunohistochemistry staining and PTEN gene expression levels to response to treatment and survival. To investigate the mechanisms of chemoresistance, one triple negative (ER/PGR/HER2 negative) and one ER positive human breast cancer cell line, where exposed to increasing doxorubicin concentrations until acquired chemotherapy resistance had evolved. The response to doxorubicin treatment in doxorubicin naive and resistant subclones was examined by Western Blotting and RT-PCR. A preclinical trial using specific inhibitors was designed based on these experiments, and we are currently evaluating the results.
We also examined PTENP1 expression levels in breast cancer biopsies and its relevance for response to treatment. PTENP1 knock down and overexpression experiments were performed, to assess the influence of PTENP1 expression level on doxorubicin cytotoxicity and tumor growth.