Date of Award

Summer 2017

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Marie McIlroy

Second Supervisor

Professor Arnold Hill

Funder/Sponsor

Breast Cancer Ireland

Keywords

Breast Neoplasms, Therapy, Aromatase, Therapeutic Use

Abstract

Introduction

Aromatase Inhibitors (AI) are the gold-standard treatment of postmenopausal breast cancer. They inhibit the conversion of androgens to estrone by CYP19 thereby blocking ligand-dependent activation of the estrogen receptor (ER). Research from our lab has identified the homeobox protein, HOXC11, as an indicator of poor response to endocrine therapy and metastases development. We aim to investigate the role of the HOXC11 target gene prosaposin (PSAP) in aromatase inhibitor resistance and assess the impact of PSAP and androgen receptor (AR) on clinical outcome.

Methods

RNA-sequencing was performed to identify HOXC11 target genes in endocrine-resistant breast cancer. Molecular biology techniques were used to validate these findings. Statistical analysis (STATA10) was used to ascertain the impact of these genes on survival rates in a cohort of breast cancer patients (n = 488).

Results

PSAP was shown to be the most significant target gene regulated by HOXC11. PSAP up-regulates AR protein expression. Down-regulation of AR reduced cell proliferation and motility in AI resistant cells. Treatment with a recombinant PSAP protein (rhPSAP) increased cell migration and invasion. Survival analysis of breast cancer patients (n = 488) showed that the intensity of AR IHC staining (> score 1) was found to inversely associate with recurrence (**p

Conclusion

HOXC11 up-regulates PSAP which promotes AR expression in AI resistance. This elucidates a novel mechanism enabling tumour utilisation of androgens for cell proliferation. AR expression is usually associated with good survival in breast cancer; however, in the AI treated population this is not the case. Thus, AR antagonists could have efficacy in treating refractory disease either alone or in combination with PI3K/mTOR inhibitors with serum secreted PSAP as potential indicator for the development of endocrine resistance and as a predictor of poor DFS.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

15.6 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2017.

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