Steroid hormone receptor profiling in human cancers: from biomarkers to novel therapeutics

  • Speaker:             Wilbert Zwart
  • Department:     Cell biology
  • Subject:              Steroid hormone receptor profiling in human cancers
  • Location:            Erasmus MC Rotterdam
  • Date:                    30-03-2017
  • Author:               Katja Slangewal

Breast- and prostate cancers are the most frequently diagnosed cancers in women and men respectively (figure 1). They are the second deathliest cancers both behind lung cancer. This makes breast- and prostate cancer an important research topic.

seminar 8 im1

Figure 1: The most frequently diagnosed cancers in male and females in the UK in 2014. According to Zwart, this graph also beholds for the rest of the world.  http://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/common-cancers-compared#heading-Zero

Approximately 75% of breast cancers and 100% of prostate cancers are related to hormonal defects. The main hormonal players are estrogen and androgen. These hormones lead to nuclear enriched transcription factors, which will cause the transcription of genes related to cell growth and division (figure 2). Both receptors complementing the estrogen and androgen receptor have a similar structure.

The relation between hormonal function and cancer is not a new concept. This relation has already been described in 1896. The treatments in that time were a little less subtle than nowadays. Cases have been described in which the entire ovary of female patients had been removed. This lead to the reduction of breast cancer, due to the removal of the estrogen source.

seminar 8 im2

Figure 2: The estrogen receptor pathway. Its stimulation leads eventually to the transcription of multiple genes and the synthesis of proteins important for cell growth and division. https://www.jci.org/articles/view/27987/figure/1

Nowadays more subtle treatments are used. The main treatment consists of tamoxifen, aromatase inhibitors or enzalutamide injections. These substances block the estrogen receptor or the nuclear import of the androgen receptor. The treatment works, but unfortunately not perfectly. This is where the research of Wilbert Zwart and his colleagues comes into play. They are looking for predictive biomarkers, which are able to tell whether the hormonal treatment will have an effect or whether it will be better to start immediately with chemotherapy.

Zwart has performed Chip-seq experiments to identify the DNA binding sites of the estrogen and androgen receptors. This led to the identification of many thousands of binding sites. Only a few of these binding sites were located at a promoter. However, most binding sites were near the start site of transcription. Zwart also found the importance of FoxA1, this protein is necessary for the estrogen/androgen receptor to be functional.

A point of consideration is related to the cell lines used for research. All cell lines are quite old and 90% of the research is done on one single cell line: MC7. This of course does not show the complexity and diversity of cancers. So Zwart decided to perform his research on newly derived tissues from recent patients. He compared the DNA binding sites of the receptors between the new tissue and MC7 cell line. Most of the binding sites did overlap. However, the necessity of FoxA1 in MC7 cell lines did not show as clearly in newly derived tissues. Zwart showed that FoxA1 is mainly present in the primary tumor, but is quite often absent in metastasis. This is an important observation, because the hormonal treatments only work in presence of FoxA1. So, this makes FoxA1 and important biomarker, to check how promising the hormonal treatment is.

Next, Zwart went back to the thousands of DNA binding sites he found. The goal is to identify the sites that matter. Individual binding sites can have a direct causal effect on proliferation. So, it is important to check them individually by making knock-outs and see what happens. The selection of specific binding sites is based on several factors. One example of these factors is whether Crispr-Cas can reach the binding site easily.

Several genes were identified nearby binding sites of the estrogen/androgen receptors. One of them is the gene FEN1. FEN1 is up regulated in breast cancer and it influences the survival after hormonal therapy. The gene is required for hormone induced gene expression, so it forms another good biomarker to test whether hormonal treatments will have an effect. In the future, more biomarkers should be identified and also be used in the clinic.

I thought the seminar was quite interesting. I really notice the difference between now and the beginning of last year, considering how much of a talk I actually understand. I liked the talk mainly because of the content. The presenting could be a bit better. I often had trouble listening, mainly because Wilbert often turned around and talked to the slides instead of to the audience. This decreased the volume a lot. Also, he had a lot of images per slide, which made the images quite small and hard to read. So sometimes the talk was hard to follow, but the main message was interesting. I had for instance no idea that most of the breast cancer research is based on one specific cell line. So I learned some new things.

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