Prof. Gosse Adema and Dr. Marleen Ansems of the Department of Tumor Immunology NCMLS together with Dr. John Martens Erasmus MC received a KWF grant (550 kE)

Ansems, Marleen

Background

Breast cancer is a common cause of cancer-related death in women. The incidence, prognosis and treatment efficacy of breast cancer are known to be affected by the nuclear receptor (NR) repertoire that breast (cancer) epithelial cells express. Especially the growth promoting and anti-apoptotic effects of the type I NRs Estrogen Receptor (ER) and Progesterone Receptor (PR) play a crucial role. Much less is known regarding type II NRs, like Retinoic-Acid-Receptor (RAR) or Peroxisome-Proliferator-Activated-Receptor (PPAR). They become activated upon binding to vitamins or metabolic products. In contrast to type I NRs, the type II NRs were reported to exhibit pro-apoptotic and anti-proliferative effects on breast tumour cells and recent data showed that RAR expression is correlated with a good prognosis. An important question is how type I NR and type II NR activities control the balance between the proliferative and apoptotic program in epithelial breast (cancer) cells.

Purpose

We recently identified the NR modulating protein called DC-SCRIPT/ZNF366 and showed that DC-SCRIPT modulates the activity of both classes of NRs, including ER and RAR. Strikingly, DC-SCRIPT inhibited the function of type I NRs while stimulating type II NR activity. DC-SCRIPT mRNA expression in breast cancer biopsies positively correlated with clinical outcome in three patients cohorts. Importantly, DC-SCRIPT constitutes an independent prognostic marker for breast cancer in another cohort of 1505 patients. Furthermore, DC-SCRIPT inhibits growth of breast cancer cellsin vitroandin vivo. We hypothesize that DC-SCRIPT activity shifts the type I/II NR balance in favour of the type II NR induced anti-proliferative and pro-apoptotic program.The overall aimis to determine the effect of DC-SCRIPT on the biological response of breast cancer cells in environments with different type I/II NR agonists and to investigate the underlying molecular mechanism(s).


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