Hormone-therapy mediated interactions between platelets and breast cancer cells: an in vitro study

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2020

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Pather, Kyrtania

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Breast cancer-associated thrombosis is a growing concern. Reciprocal interactions between platelets and tumour cells facilitate tumour progression, ultimately leading to thromboembolic complications. Treatment strategies including hormone-therapies are associated with increased thrombotic risk. However, in vitro studies found that Tamoxifen reduces thrombotic risk, contradictory to clinical evidence; with little evidence on the mechanistic effects of Anastrozole. Furthermore, while hormone-dependent tumours are treated with hormone therapy based on the presentation of the oestrogen receptor (ER), ERα, little is understood regarding ERβ. This study developed an in vitro system to mimic the effects of cumulative hormone-therapy (Anastrozole or Tamoxifen) by pre-treating MCF7 and T47D cells with hormone-therapy (Model 1) prior to exposure to whole blood (WB). Early stages of platelet activation described using CD62P expression and ultrastructure, and associated cancer cell ER (ESR1 and ESR2) gene expression were assessed. The study was then expanded to include an additional model to recapitulate circulatory effects of hormone therapy (Model 2) where blood constituents (WB, platelet-rich plasma and platelet-poor plasma) were pre-treated prior to exposure to cancer cells. Hypercoagulation was assessed as a function of thrombin activity, CD62P and CD63 expression defined by an index of platelet activation, and corresponding ultrastructure. Furthermore, ER protein expression was determined and correlated with hypercoagulation markers to assess whether tumour profiles and hypercoagulation were associated. Breast cancer cells induced hypercoagulation, compounded by hormone-therapy regardless of Model employed, but dependent on cellular subphenotype. Furthermore, ER expression altered, highlighting subphenotypic differences; with T47D cells, having greater ERβ expression. We postulate this profile is associated with the induction of a hypercoagulatory environment under Anastrozole treatment. Additionally, it was determined that Tamoxifen treatment induces a hypercoagulatory environment. This not only compares with clinical studies indicating a greater thrombotic risk for patients undergoing hormone-therapy treatment but highlights that subphenotypes, which clinically would be treated similarly, may be associated with differing thromboembolic profiles. The present study provides a framework and ex vivo models in which to undertake further research, to complement our findings regarding breast tumour subphenotype heterogeneity and to determine other biomarkers that may be predictive of hypercoagulatory risk

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A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Health Sciences, School of Anatomical Sciences, University of the Witwatersrand, Johannesburg, 2020

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