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

Sanabria Figueroa, Eduardo (2017)

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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 PI3K signaling p. 11 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

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