Kuruppu, Anchala
(2016)
The role of HER family signalling in breast cancer.
PhD thesis, University of Nottingham.
Abstract
The HER family of receptors plays a major role in a variety of cancers including breast cancer. Several researchers have shown that HER family overexpression in breast cancer is a significant prognostic factor, especially for survival and relapse. Therefore, many therapeutics are being developed to test the impact of HER family blockade in breast cancer. Although numerous therapies have been developed, many have not been very successful in the clinic. This is often a consequence of cancer cells developing new mechanisms to activate HER family signalling indirectly through cross talk with compensatory pathways. Thus, it is vital to consider the biology of the HER signalling network to a greater extent, which includes RAS/MAPK, PI3K/AKT, mTOR, JAK/STAT, ER and AhR pathways and, also identify breast cancer patient populations that will benefit from specific targeted therapies that target these pathways.
In the current study, 6 breast cancer cell lines (MCF7, T47D and ZR-75-1, SKBR3, MDA-MB 468 and MDA-MB 231) representing distinct molecular subtypes of breast cancer have been used to investigate anti-cancer effects of a variety of agents. These agents include clinical as well as currently experimental and entirely novel pharmacological agents alone or in combination. Among the clinical agents studied, it was found that EGF and Gefitinib were significantly potent against the HER2 overexpressing SKBR3 cell line, out of the panel of cell lines studied. EGF and Gefitinib showed a slightly different spectrum of activity from each other against the SKBR3 cell line. However, more research is needed to determine whether EGF could be used as a therapy for HER2 overexpressing breast cancer. Even though Gefitinib is currently used as a treatment in the clinic, the therapeutic window of this agent is drastically narrowed by its poor bioavailability, acquired resistance and systemic toxicity. Thus, in the current study, encapsulation of Gefitinib within the cavity of human heavy chain (H) apoferritin (AFt), provided a route for sustained release of Gefitinib from the H-AFt cavity, which demonstrated enhanced anti-tumour activity, at a longer duration against the SKBR3 cell line compared to Gefitinib alone.
Overexpression of HER2 is considered to confer a more aggressive phenotype in breast cancer. Many patients have shown resistance to existing clinical agents such as Trastuzumab, demonstrating the need for novel therapies. Hence, 2 novel HER2 targeting human H and light chain (L)-AFt-fusion proteins were tested, and it was found that the nanoagent - H-AFt-fusion protein was very potent against the SKBR3 cell line compared to the L-AFt-fusion protein. This novel H-AFt-fusion protein abolished SKBR3 colony formation completely, caused a G1 arrest and a reduction in the orchestration of S and G2/M cell cycle events and also induced a large SKBR3 apoptotic population demonstrating its potent cytotoxic effects. Furthermore, this agent down-regulated the HER2 protein remarkably which resulted in significant down-regulation of the RAS/MAPK, PI3K/AKT and JAK/STAT signal transduction pathways in SKBR3 cells.
Previous research has shown that a combination of pharmacological agents are more effective against cancer than individual agents due to up-regulation of compensatory signalling pathways which cancer cells use to thrive and acquire resistance to agents. Thus, several agents were tested in combination. Out of the agents tested it was found that 3 dual PI3K/mTOR inhibitors were potent against the triple negative breast cancer cell line - MDA-MB 468 and the HER2 overexpressing SKBR3 cell line. Further, Gefitinib in combination with an experimental AhR ligand - 5F 203, showed synergistic growth inhibition against the SKBR3 cell line by inducing CYP1A1, thereby resulting in a large apoptotic population. It was observed that the effect of Gefitinib was mainly potentiated by the effect of 5F 203 within the agent combination.
There is a momentous unmet medical need for the development of effective therapies that can stabilise or slow the progression of breast cancer, therefore, these results may contribute to existing knowledge or enhance further understanding of the HER signalling network and therapies targeting this network. It may also guide potential treatment options which might lead to significant improvements in breast cancer therapy in the clinic thereby personalising therapy for patients with breast cancer.
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