Functional and mechanistic properties of lapatinib in selective breast cancer cells

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Cock, Ian E

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Khanna, Kum Kum K

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2021-02-10
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Abstract

Breast cancer is a complex heterogenous disease with distinct molecular subtypes and metabolic behaviour, disparate responses to therapies, and considerable differences in the overall survival of the patients. Insights into the biological heterogeneity of the disease has led to the development of therapeutic strategies for the effective treatment of breast cancer. The current treatment options include hormone therapy for estrogen positive (ER-positive); anti-HER2 antibody (trastuzumab) therapy for human epidermal growth factor receptor 2 (HER2)-amplified, and general chemotherapy for triple-negative (TN) breast cancers. Unfortunately, therapeutic outcomes remain poor due to inherent or acquired resistance of the cells to the treatments and the toxicity associated with therapy. Metabolic adaptation of breast cancer cells is considered to play a crucial role in enabling the cells to become resistant to therapy and acquire metastatic potential. Bioenergetic alteration (the Warburg effect) is fundamental to all forms of cancer and is regarded as one of the hallmarks. The Warburg effect is characterized by the presence of glycolytic phenotypes within the tumor tissue. Like most cancers, an increase in lactate production observed in breast cancers may be related to the upregulation of lactate dehydrogenase (LDH) enzyme that catalyses the conversion of pyruvate to lactate. Recently, human RasGAP -SH3 domain binding protein (G3BP), an RNA binding protein, was shown to interact with the mRNA of mitochondrial H+-ATP synthase subunit β (β-F1-ATPase), an enzyme that the mediates ATP production through oxidative phosphorylation in mitochondria. That study implicated the role of G3BP in the glycolytic phenotype observed in cancers. Indeed, G3BP is overexpressed in all forms of cancers including breast cancer. The focus of this study was to investigate the potential relevance of G3BP-1 as a breast cancer biomarker and targeting G3BP-1 by lapatinib (Lap) to inhibit the morphological adaptation and cell migration of SKBR3 breast cancer cell line. Whilst, much of the signaling mechanisms have been elucidated, the role of G3BP in the glycolytic switch remains elusive. [...]

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Thesis (PhD Doctorate)

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Doctor of Philosophy (PhD)

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School of Environment and Sc

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The author owns the copyright in this thesis, unless stated otherwise.

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Subject

Breast cancer

biomarker

human RasGAP -SH3 domain binding protein

G3BP

SKBR3

lapatinib

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