A role for Interleukin-1 receptor-associated kinase 1 (IRAK1) in promoting tumour growth and metastasis has been identified in recent years, across several aggressive cancer subtypes (Rhyasen et al. 2013, Wee et al. 2015, Dussiau et al. 2015). In certain cases, this has been linked to already recognized mechanisms associated with IRAK1 from its role in regulating immune responses, such as NF-κB activation (Wee et al. 2015). However, novel roles for IRAK1 in driving tumour growth have been identified that are unrelated to any previously defined role, including inhibiting PIDDosome-mediated apoptosis (Liu et al. 2019). This study showed that IRAK1 expression was elevated in tamoxifen-resistant (Tam-R) ER+ breast cancer, with IRAK1 knockdown significantly reducing the growth of Tam-R cells as assessed by 2D and 3D growth assays. Additionally, IRAK1 knockdown impaired the agonistic effects that tamoxifen has on the growth of Tam-R cells and re-sensitizes the cells to tamoxifen. This work identified a novel role for IRAK1 in regulating HER family expression in response to tamoxifen treatment, a significant finding as all members of the HER family have been linked to tamoxifen resistance previously (Britton et al. 2006, Cui et al. 2012, Thrane et al. 2013, Wege et al. 2018). Further, we identified an important role for IRAK1 in Aurora kinase A (Aurora-A) activation in response to tamoxifen treatment. Aurora-A activity has been linked to aggressive tumour growth and poor patient prognoses across a number of cancer subtypes, with Aurora-A inhibition being extensively studied as a potential therapeutic option (Bavetsias and Linardopoulos 2015). This study also examined the efficacy of using drugs that inhibit IRAK1 and JNK family kinases, alone or in combination, as novel therapeutic options for Tam-R breast cancer. JNK has already been linked to treatment resistance in TNBC and pancreatic cancer (Ebelt et al. 2017, Lipner et al 2020). We found that IRAK1 and JNK inhibition alone reduced Tam-R ER+ breast cancer cell growth, with less marked effects observed for tamoxifen-sensitive (Tam-S) cell lines with JNK specific inhibitors, as assessed by 2D and 3D cellular assays. However, combined inhibition of IRAK1 and JNK synergized to potently inhibit Tam-S and Tam-R ER+ breast cancer cell growth. These findings support progressing this research to in-vivo models of Tam-S and Tam-R ER+ breast cancer, as well as other breast and aggressive cancer subtypes. Overall, this work has identified a novel role for IRAK1 in tamoxifen-resistant breast cancer and indicated the potential therapeutic benefits of targeting IRAK1 in this cancer subtype.