A new therapeutic target to facilitate radioiodine treatment of breast cancer

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Poole, Vikki Louise (2017). A new therapeutic target to facilitate radioiodine treatment of breast cancer. University of Birmingham. Ph.D.

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Abstract

The development of new therapeutic strategies for breast cancer is urgently needed. Exploitation of radioiodide uptake by the overexpressed sodium iodide symporter (NIS) has been widely proposed as a novel therapeutic strategy. However, radioiodide uptake is insufficient for tumour destruction. The proto-oncogene PBF binds NIS and inhibits its plasma membrane retention, thereby repressing critical radioiodide uptake in thyroid cancer. This thesis demonstrated that PBF, also upregulated in breast cancer, similarly repressed NIS in breast cancer cells, where phosphorylation of PBF at Y174 was key to NIS interaction and could be disrupted via treatment with the Src inhibitor dasatinib. Mutation of a predicted Src consensus sequence (EEN/AAA170-172AAA) abrogated pY174 PBF and radioiodide uptake repression. In the presence of dasatinib-resistant Src (T341I), dasatinib no longer rescued PBF repression of NIS, indicating that Src specifically mediates PBF phosphorylation. Inhibition of N-myristoylation also significantly increased radioiodide uptake. Combined Src and myristoylation inhibition induced a ~70% increase of radioiodide uptake in the absence of PBF overexpression. Thus, disrupting Src phosphorylation of PBF by targeted mutagenesis and Src kinase inhibition reveal radioiodide uptake into breast cancer cells can be significantly enhanced through therapeutic approaches focused on Src:PBF:NIS and myristoylation, making radioiodide treatment of breast cancer potentially viable.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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