Elucidating activity for WNT signaling mediators in breast cancer and Paclitaxel chemoresistance

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Breast cancer continues to be among the most common cancers found in patients worldwide with more than 300,000 new cases projected to be diagnosed in 2024 for women in the United States (Siegel et al. 2023). Metastatic breast cancer is heterogenous, which indicates both its complexity and the increased degree of chemotherapeutic intervention necessary for advanced or refractory cases. The development of chemoresistance further complicates intervention, as even previously effective therapeutics against early-stage cancers can develop resistance and generate refractory, high-grade tumors. Paclitaxel is a microtubule-stabilizing compound that remains of clinical importance due to its ongoing applications in early and metastatic disease. Studies in paclitaxel chemoresistance remain of critical consideration as even this promising therapeutic has been shown, like all compounds, to result in chemoresistance (Steding 2016). Studies have demonstrated pivotal roles for the WNT signaling pathway within tumor development, progression, and acquired chemoresistance (Zhong and Virshup 2019). The WNT signaling pathway has been implicated as a driving mechanism of chemoresistance in several cancer types, including both early and metastatic breast cancer. As WNT signaling can increase both as an immediate response to Paclitaxel treatment and as a potential mechanism of paclitaxel chemoresistance, it is important to elucidate further whether WNT signaling is actually a driving force of chemoresistance or merely a byproduct of its development. Furthermore, the widespread mechanisms and players involved in WNT signaling require further isolation and consideration to determine the most significant players in chemoresistance. Prior evidence has indicated that reductions in WNT signaling have the potential to restore sensitivity to treatment to a wide range of chemotherapeutics for some cancer types (Chikazawa 2010). These findings may be cell type specific or be a consequence of specific changes of WNT signaling mediators rather than global WNT signaling. Preliminary evidence observed in paclitaxel chemoresistant cell populations indicated a wide range of changes in WNT signaling mediators including both downregulation and upregulation of components within the same pathway. With the potential for conflicting results across cancers and these preliminary findings in mind, further investigation into the role of WNT signaling mediators in paclitaxel sensitivity and resistance remains of significant interest. In order to define actual mechanisms of action, roles for global WNT signaling as well as specific roles for key players within the pathway must be confirmed. We hypothesized that changes in global WNT signaling would significantly alter breast cancer sensitivity to paclitaxel through both canonical and noncanonical pathways via specific mediators. To begin to assess this hypothesis, breast cancer cells were treated with a global WNT inhibitor or an inhibitor targeting Beta-catenin (β-catenin). Treatment of cells with both inhibitors were found to suppress overall WNT activity to similar levels; however, the targeting of β-catenin altered paclitaxel effcacy compared to paclitaxel alone or in combination with the global inhibitor. Further analysis of specific changes following the combined treatment implicated the noncanonical pathway as playing a more substantial role in paclitaxel sensitivity. Although investigations remain ongoing, these findings indicate novel behaviors for WNT signaling in paclitaxel sensitivity and support further exploration into the complicated world of WNT signaling and its signaling mediators in chemoresistance. This research was supported in part by an Indiana Academy of Sciences Senior Research Grant (IASSG-S21-07) as well as a Marian University Faculty Research Development Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.