A study of the influence of hormones and growth factors to the accessible chromatin landscape in human breast cancer

摘要

Mitogens are substances capable of inducing cell proliferation. Upon binding to their receptors a signal pathway is activated resulting in gene transcription and cell proliferation. These signals are usually carefully regulated, but cancer cells lack this regulation and the result is uncontrolled cell division. Breast cancer is the most common cancer among women in the western world. Several subtypes are involved depending on which receptor is overexpressed, each type with its own expression, treatment and prognosis. FoxA1 is a protein functioning as a pioneer factor due to its chromatin remodeling ability, so receptors like estrogen receptor can bind to estrogen responsive elements (ERE) on the DNA and start transcription of estrogen target genes. The treatment of breast cancer depends on the subtype, but the women do not always respond to treatment without a clear reason. Due to this, it is interesting to explore if the hormones, like estrogen and androgen, or growth factors, like heregulin and epidermal growth factor, are independently able to remodel the chromatin or if the presence of FoxA1 is necessary. This project was conducted with a method called FAIRE, which isolates the nucleosome free DNA, the part of DNA supposedly active during transcription. When the DNA is not being transcribed it is densely packed in nucleosomes. The results show that growth factors are able to open several regions while the hormones are more active in closing them. All the hormones and growth factors are more or less affected by FoxA1.