The Role and Function of MYB in Human Breast Cancer

Yvette Drabsch (2011). The Role and Function of MYB in Human Breast Cancer PhD Thesis, UQ Diamantina Institute, The University of Queensland.

       
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Author Yvette Drabsch
Thesis Title The Role and Function of MYB in Human Breast Cancer
School, Centre or Institute UQ Diamantina Institute
Institution The University of Queensland
Publication date 2011-05
Thesis type PhD Thesis
Supervisor Professor Thomas Gonda
Doctor Melissa Brown
Total pages 333
Total colour pages 51
Total black and white pages 282
Subjects 11 Medical and Health Sciences
Abstract/Summary Breast cancer is one of the most common malignancies in women. It continues to be a major burden and cause of death among women worldwide. This project investigated the role and function of the oncogene, MYB, in human breast cancer. Even though there are only a few studies that have investigated MYB in breast cancer, they have provided a series of observations that make a strong prima facie case for the causative involvement of MYB in breast cancer. Further investigation was needed to move from the correlative and circumstantial evidence that surrounds this oncogene in breast cancer. Based on the evidence surrounding the potential role of MYB in breast cancer, this project examined the hypothesis that MYB contributes to mammary carcinoma. This project hypothesized that in breast cancer cells, transcriptional attenuation occurs within the first intron of MYB. It was also hypothesized that the estrogen receptor (ER) is capable of overcoming the transcriptional attenuation. It is shown that the estrogen-mediated control of MYB is via a transcriptional attenuation site within the first intron. Furthermore, it is shown that estrogen leads to binding of ER within a region adjacent to the transcriptional attenuation motif and overcomes the elongation block. The second aim was to determine whether MYB is required for the growth of ER positive tumour cells in vitro and in vivo. By using antisense oligonucleotides and RNA interference to block MYB expression it was discovered that MYB was required for the proliferation of ER positive breast cancer cells. This provided the first functional evidence of a role for MYB in breast cancer. Furthermore, xenograft experiments were used to study the effect of MYB inhibition on tumour growth. The data from the xenografted tumours indicated that MYB knockdown leads to a significant decrease in tumour growth as compared to the control xenografts. As part of the second aim, the pattern of MYB expression in breast cells undergoing differentiation was examined. To further understand the function of MYB in breast cancer and in mammary epithelial cells (MECs) generally, its role in the differentiation of mammary carcinoma cells and MECs were examined. Differentiation of human breast cancer cell lines and non-tumorigenic MECs can be induced by chemical agents or lactogenic hormones, respectively. It was confirmed that, like some other cancer cells (such as haematopoietic cells, and the epithelial colon cells), that MYB expression decreases during the process of differentiation in mammary carcinoma cells and MECs. A functional role for MYB in MEC differentiation was further implied by the effects of MYB knockdown on breast cancer cell lines. While a small degree of differentiation was observed with an inducible MYB shRNA alone, a more dramatic effect was apparent with MYB knockdown and (otherwise) marginally-effective concentrations of differentiation inducing agents (DIAs), which resulted in essentially complete differentiation. Conversely, enforced MYB expression was able to block differentiation of both carcinoma cells and non-tumorigenic MECs, again strikingly paralleling MYB’s activities in other cell systems. Finally, the third aim was to ascertain if high levels of MYB expression can lead to breast tumours. This required the generation of transgenic mice which overexpressed Myb specifically in the mammary gland. Given the importance of estrogen and its receptor in the pathogenesis, as well as treatment, of this disease, a transgenic mouse model which would allow the development of ER+ tumours was preferred. The neu-related lipocalin (NRL) promoter has been shown previously to develop mammary adenocarcinomas that are ER α positive and negative, similar to human disease. As such, the NRL promoter was used to study the interaction between Myb and estrogen in disease development and progression. Preliminary investigation on the founder mice showed promising results, but, further investigation are necessary before any conclusions may be drawn. This project has shown that MYB is an effector of estrogen/ER signalling and this has provided the first demonstration of a functional role of MYB in human breast cancer. Also, it has been shown that MYB plays an important role in regulating the balance between proliferation, differentiation, and apoptosis in mammary epithelial cells.
Keyword Myb
Breast cancer
Transcription
apoptosis
Differentiation
Xenograft
Transgenic Mice
Rnai
Proliferation
Additional Notes Pages in Colour: 9, 13, 17, 19, 25, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, , 129, 147, 149, 154, 156, 159, 187, 188, 189, 191, 206, 211, 212, 215, 216, 217, 220, 229, 234, 237, 248, 250, 251, ,253, 255, 256, 257, 271, 278, 292, 293, 296, 298, 299, 305, 309 Pages in Landscape: 174

 
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Created: Fri, 03 Jun 2011, 06:59:54 EST by Ms Yvette Drabsch on behalf of Library - Information Access Service