Mechanisms of insulin-like growth factor 1 receptor-mediated trastuzumab resistance in human epidermal growth factor receptor 2-overexpressing breast cancer 公开

Abstract

Breast cancer is one of the most common types of cancer among American women. Approximately 20% of metastatic breast cancer cases are classified as the HER2 subtype, characterized by HER2 gene amplification or protein overexpression. Trastuzumab, a humanized monoclonal antibody against HER2 extracellular domain IV, has been used for the treatment of HER2-positive breast cancer. However, resistance to trastuzumab develops within a year of treatment. Increased expression or compensatory signaling through IGF-1R has been associated with resistance to trastuzumab, but the molecular and biological mechanisms through which IGF-1R promotes resistance or disease progression remain unclear. Furthermore, IR has also been suggested to contribute to trastuzumab resistance, by crosstalk with IGF-1R or the formation of hybrid receptors. This dissertation identified cell invasion as the main biological effect elicited by the crosstalk of IGF-1R and HER2 in two HER2-overexpressing cells lines. Src and FAK kinases emerged as regulators of invasion downstream of IGF-1R signaling in HER2-overexpressing cells, as demonstrated by decreased invasion of cells treated with Src and FAK kinase inhibitors in the presence of IGF-1 stimulation. Transcription factor FoxM1 was also identified as an important mediator of invasion in trastuzumab-resistant cells, for FoxM1 knockdown decreased invasion of resistant cells stimulated with IGF-1, and FoxM1 overexpression blocked the anti-invasive effect of IGF-1R knockdown and trastuzumab treatment. Our results also support that IR is a mediator of invasion in HER2-overexpressing cells, similarly to IGF-1R. We demonstrate for the first time that insulin-mediated activation of IGF-1R/IR phosphorylates HER2 in breast cancer cells with primary resistance to trastuzumab, similar to IGF-1-mediated phosphorylation of HER2. Additionally, IGF-1 stimulation blocked the anti-invasive effect of transient IR knockdown and trastuzumab treatment, while insulin stimulation overcame the anti-invasive effect of stable IGF-1R knockdown and trastuzumab treatment. All together, our findings confirm that IGF-1R and IR contribute to trastuzumab resistance in HER2-positive breast cancers. Our results strongly suggest that co-targeting IR, IGF-1R, and HER2 is a rational approach for patients whose breast tumors demonstrate IGF-1R/IR activation and HER2 overexpression and have progressed on prior trastuzumab treatment.

Table of Contents

Chapter 1: Background p. 1

1.1 Cancer p. 2
1.2 Breast Cancer p. 3
1.3 HER2-positive breast cancer p. 6
1.3.1 HER2 receptor p. 6
1.3.2 HER2 signaling p. 11
1.3.2.1 PI3K signaling p. 11
1.3.2.2 MAPK signaling p. 15
1.4 Targeted therapies for the treatment of HER2-positive breast cancer p. 17
1.4.1 Trastuzumab p. 17
1.4.2 Lapatinib p. 19
1.5 Insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) signaling as mechanisms of resistance to trastuzumab in breast cancer p. 20

1.5.1 IGF/Insulin system p. 20
1.5.2 IGF-1R in breast cancer p. 21
1.5.3 IR in breast cancer p. 25
1.5.4 IGF-1R/IR hybrid receptors in breast cancer p. 26
1.6 Targeting IGF-1R and IR in breast cancer p. 26
1.7 Scope of this dissertation p. 28

Chapter 2: Insulin-like growth factor-1 receptor signaling increases the invasive potential of HER2-overexpressing breast cancer cells via Src-FAK and FoxM1 p. 31

2.1 Introduction p. 32
2.2 Materials and Methods p. 34
2.3 Results p. 41
2.4 Discussion p. 73

Chapter 3: Insulin receptor and insulin-like growth factor-1 receptor signaling promotes HER2 phosphorylation and invasion of trastuzumab-resistant breast cancer cells p. 79

3.1 Introduction p. 80
3.2 Materials and Methods p. 83
3.3 Results p. 87
3.4 Discussion p. 104

Chapter 4: Conclusions p. 109
4.1 Summary p. 110
4.2 Future Directions p. 115

Chapter 5: References p. 120

About this Dissertation

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Molecular & Systems Pharmacology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Pharmacology Biology, Molecular Health Sciences, Oncology
关键词	Drug resistance Cell invasion Breast cancer Insulin receptor Trastuzumab HER2 positivity IGF-1R
Committee Chair / Thesis Advisor	Nahta, Rita, Emory University Yang, Lily, Emory University
Committee Members	Kang, Sumin, Emory University Hepler, John R, Emory University

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