Insulin-like growth factor receptor 1(IGFIR) is overexpressed in a subset of triple negative breast cancers

Insulin-like growth factor binding protein-3 (IGFBP-3) is a key regulatory molecule of the IGF axis and can function in a tissue-specific way as both a tumor suppressor and promoter. Triple-negative breast cancer (TNBC) has high tumor expression of IGFBP-3 associated with markers of poor prognosis and, although accounting for 15–20% of all breast cancers, is responsible for disproportionate rates of morbidity and mortality. Because they lack estrogen and progesterone receptors and overexpression of HER2, TNBC are resistant to treatments that target these molecules, making the development of new therapies an important goal. In addition to frequent high expression of IGFBP-3, these tumors also express EGFR highly, but targeting EGFR signaling alone in TNBC has been of little success. Identification of a functional growth-stimulatory interaction between EGFR and IGFBP-3 signaling prompted investigation into cotargeting these pathways as a novel therapy for TNBC. This involves inhibition of both EGFR kinase activity and a mediator of IGFBP-3’s stimulatory bioactivity, sphingosine kinase-1 (SphK1), and has shown promise in a preclinical setting. Functional interaction between EGFR and IGFBP-3 may also promote chemoresistance in TNBC, and delineating the mechanisms involved may identify additional targets for development of therapies in cancers that express both IGFBP-3 and EGFR.

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Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

Endocrine Related Cancer ◽

10.1530/erc-16-0218 ◽

2016 ◽

Vol 23 (11) ◽

pp. R527-R550 ◽

Cited By ~ 10

Author(s):

Aleksandra M Ochnik ◽

Robert C Baxter

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Cancer Therapy ◽

Therapeutic Target ◽

Growth Factor Receptor ◽

Insulin Like Growth Factor ◽

Breast Cancers ◽

Downstream Signaling ◽

Intrinsic Complexity ◽

Igf1r Signaling

Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity  and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers.

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Metabolic Syndrome and Triple-Negative Breast Cancer: A New Paradigm

International Journal of Breast Cancer ◽

10.1155/2012/809291 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 41

Author(s):

Andrew A. Davis ◽

Virginia G. Kaklamani

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Growth Factor ◽

Triple Negative ◽

Growth Factor Receptor ◽

Breast Cancers ◽

New Paradigm ◽

Cancer Subtypes ◽

The Metabolic Syndrome

Triple-negative breast cancers (TNBCs) are aggressive tumors with poor prognosis compared to other breast cancer subtypes. The evidence linking TNBC with the metabolic syndrome, which consists of central obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, has emerged from clinical studies and experiments using cell lines and mouse models. Epidemiological studies have associated abdominal obesity with increased incidence of TNBC. Additionally, insulin resistance, dyslipidemia, and hypertension are associated with increased incidence of breast cancer across all subtypes. The insulin-leptin-adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis. Specifically, increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation, survival, cell-cycle regulation, and angiogenesis. Insulin, insulin-like growth factor I (IGF-I), and epidermal growth factor receptor (EGFR) may mediate interactions between these two hormones. Further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin-leptin-adiponectin axis for TNBC.

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