Abstract 92: tGLI1 and IL-6/IL-6R/GP130/STAT3 pathways cooperate to promote breast cancer stem cells and are co-activated in HER2-enriched and triple-negative breast cancers
Authors: Manore Sara G. , Doheny Daniel L. , Zhu Dongqin , Wong Grace L. , Regua Angelina T. , Arrigo Austin , Wagner Calvin J. , Najjar Mariana , Lo Hui-Wen 
Published: June 2022

Breast cancer is the most frequently diagnosed cancer and second leading cause of cancer-related deaths in women; 30% of primary breast cancer cases will develop distant metastases. The majority (90%) of breast cancer-related deaths are due to distant metastases. HER2-enriched breast cancer and triple-negative breast cancer (TNBC) have the highest propensity to metastasize and have limited to no treatment options. Metastatic HER2-enriched breast cancer and TNBC patients commonly develop therapeutic resistance and, therefore, lack efficacious therapies. Due to dismal prognoses in metastatic HER2-enriched breast cancer and TNBC patients, there remains an urgent need to identify novel molecular pathways for actionable therapeutic targets. Truncated glioma-associated oncogene homolog 1 (tGLI1), an alternatively spliced variant of GLI1, is a gain-of-function tumor-specific terminal effector in the Hedgehog pathway. tGLI1 promotes breast cancer growth and circulating tumor cells to the brain. More recently, our lab has reported tGLI1 physically interacts with Signal Transducer and Activator of Transcription 3 (STAT3); tGLI1 and STAT3 are co-overexpressed in node-positive HER2-enriched and triple-negative breast carcinomas. The Interleukin-6 (IL-6) signaling axis is a primary regulator of STAT3 and is frequently dysregulated and hyperactivated in multiple cancers, including breast cancer. IL-6 functions through a hexameric receptor complex comprised of IL-6 receptor α (IL-6R) and glycoprotein 130 (GP130) to recruit Janus tyrosine kinases (JAK). In turn, JAKs phosphorylate STAT3 resulting in homodimerization, nuclear translocation, and transcriptional activity. Independently, tGLI1 and IL-6/IL-6R/GP130/STAT3 pathways have been previously investigated as mediators for breast cancer metastases; however, whether they cooperate to promote breast cancer progression remains unknown. Herein, we report tGLI1 and IL-6/IL-6R/GP130/STAT3 pathways to be frequently co-expressed and co-activated in HER2-enriched breast cancer and TNBC tumors and that the co-activation is associated with a shortened metastasis-free survival (MFS). Additionally, when stratified by metastatic site, breast tumors with high tGLI1 and IL-6/IL-6R/GP130/STAT3 co-activation are associated with a worse bone, brain, and lung MFS compared to tumors with low co-activation. Ectopic co-overexpression of tGLI1 and GP130 upregulates mRNA expression of stemness genes, Nanog, Sox2, and Oct4, leading to the subsequent promotion of the breast cancer stem cell (CSC) subpopulation in vitro. Taken together, our findings revealed a novel crosstalk between tGLI1 and the IL-6/IL-6R/GP130/STAT3 signaling axis to enhance the CSC subpopulation, suggesting the importance of the crosstalk in mediating metastasis of HER2-enriched breast cancer and TNBC.

Citation Format: Sara G. Manore, Daniel L. Doheny, Dongqin Zhu, Grace L. Wong, Angelina T. Regua, Austin Arrigo, Calvin J. Wagner, Mariana Najjar, Hui-Wen Lo. tGLI1 and IL-6/IL-6R/GP130/STAT3 pathways cooperate to promote breast cancer stem cells and are co-activated in HER2-enriched and triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 92.