The role of inhibitor of DNA binding 4 (Id4) in mammary gland development and breast cancer

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Copyright: Junankar, Simon
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Abstract
The inhibitor of DNA binding (Id) proteins Id1-4 are transcriptional regulators that control many cell fate and developmental processes and are often deregulated in cancer. In this dissertation I examine the role of Id proteins in mammary development and neoplasia. Initially the role of Id1 in regulating the immune response to senescent tumour cells was examined, before a more thorough investigation into the role of Id4 during mammary gland development and breast cancer. Prior to the studies described in this thesis, the role for Id4 during mammary gland development had not been investigated and its role in breast cancer was controversial. Id4 expression patterns in the mammary gland were analysed throughout development by immunohistochemistry and the phenotype of Id4 loss was determined using the Id4 knockout mouse. The function of Id4 was further analysed using the normal mouse mammary epithelial cell line Comma-Db. Id4 expression was examined in breast cancer cell lines and a number of cohorts of breast cancer patients. The results presented here show that Id4 is a critical regulator of mammary gland development through its control of differentiation, proliferation and extracellular matrix (ECM) remodelling pathways. Id4 expression is restricted to the myoepithelial cells of the mammary gland and its loss leads to impaired mammary gland development. Overexpression and knockdown studies utilising the Comma-Db cells demonstrated that Id4 inhibited luminal differentiation and was required for cell proliferation. Furthermore Id4 overexpression promoted neoplastic transformation of the normal Comma-Db cell line in vivo. Transcript profiling experiments further demonstrated Id4 regulated a number of ECM remodelling genes. Our results from examining patient cohorts demonstrate that Id4 expression associates with the Her2 and basal-like subtypes of breast cancer and that high expression significantly correlates with improved patient survival. Despite high Id4 expression associating with improved survival, our combined results demonstrate that Id4 nonetheless has the capacity to promote tumourigenesis.
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Author(s)
Junankar, Simon
Supervisor(s)
Swarbrick, Alexander
Ormandy, Christopher
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Publication Year
2012
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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