Date of Award

6-2016

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Jochen Prehn

Second Supervisor

Professor Derek LeRoith

Funder/Sponsor

The Lucy G. Moses Fund, Department of Medicine, Mount Sinai. NIH/NCI 1K08CA190770

Keywords

Diabetes Mellitus, Diabetes Mellitus Type 2, Hyperinsulinism, Breast Cancer

Abstract

Obesity, type 2 diabetes and the metabolic syndrome are associated with an increased risk of developing breast cancer. In addition, these conditions are associated with more aggressive forms of breast cancer and greater breast cancer mortality. All three conditions are associated with insulin resistance and endogenous hyperinsulinemia. Breast cancers express the insulin receptor (IR), therefore we hypothesize that endogenous hyperinsulinaemia promotes breast cancer growth and metastases by acting directly on the IR on the tumour cells, and by causing epithelial to mesenchymal transition in the tumour. We found that hyperinsulinaemia led to increased growth and metastasis of both murine and human breast cancers in an animal model of hyperinsulinaemia. We found that the increase in tumour metastasis was associated with increased vimentin expression in the primary tumours. We found that silencing the IR reduced the growth of human breast cancer xenografts in the animals, associated with a decrease in vimentin expression. Silencing vimentin in breast cancer cells reduced their ability to invade in vitro and decreased their metastatic capabilities in the hyperinsulinaemic mice. Examining human breast cancer cell lines, we found that triple negative breast cancer cell lines had higher IR expression than oestrogen receptor positive breast cancer cell lines, and that the main isoform of the IR in both human breast cancer specimens and cell lines was the IR-A isoform. Higher levels of IR-A and lower levels of IR-B correlated with changes in the expression of splicing factors, SRSF3 and MBNL2 in both the breast cancer cell lines and the human breast cancer specimens. We found that none of the insulin analogues in clinical use increased tumour growth, but a mitogenic analogue AspB10 stimulated tumour growth by activating the IR. These data show that endogenous hyperinsulinaemia and IR signaling are important regulators of breast cancer growth and progression.

Creative Commons License

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

File Size

10.2 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2016.

Available for download on Friday, June 01, 2018

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