Abstract 1039: TrkA and JAK2-STAT3 pathway crosstalk promotes breast cancer stem cells in HER2-enriched and triple-negative breast cancers
Authors: Regua Angelina T. , Zhu Dongqin , Doheny Daniel L. , Wong Grace L. , Manore Sara G. , Wagner Calvin J. , Arrigo Austin , Najjar Mariana , Lo Hui-Wen 
Published: June 2022

Breast cancer is the most commonly diagnosed cancer in American women and accounts for ~15% of cancer-related deaths. Despite the current standard of care, metastatic HER2-enriched breast cancer and triple-negative breast cancer remain difficult to treat due to poor response to treatment, lack of actionable targets, or eventual acquired resistance. The high mortality rate of metastatic HER2-enriched breast cancers and triple-negative breast cancers highlights the need for novel actionable targets for improved response to therapeutic intervention. Through datamining of publicly available breast cancer patient datasets, we recently found that Tropomyosin receptor kinase A (TrkA) and Janus kinase 2 (JAK2)-STAT3 pathways are co-activated and co-enriched in HER2-enriched breast cancers and triple-negative breast cancers (Cancers 10:2340-2360, 2021). We also found that TrkA, a receptor tyrosine kinase, directly interacts with and phosphorylates STAT3 on Y705 residue, resulting in STAT3 activation, nuclear translocation, and increased transcription of STAT3 target genes SOX2 and c-MYC, which are associated with breast cancer stem cell formation as well as tumor recurrence and metastasis. In this study, we aimed to further characterize the effects of the TrkA-JAK2/STAT3 pathway crosstalk on breast cancer stem cells. Our data showed that overexpression of TrkA enhances mammosphere formation and ALDH activity of breast cancer cells, which are further enhanced upon co-overexpression of STAT3. Our study further revealed that TrkA and JAK2 inhibitors synergize to reduce breast cancer stemness since co-inhibition of TrkA and JAK2 significantly reduces the CD44high/CD24low cell subpopulation, mammosphere formation, and ALDH activity to a greater extent compared to vehicle or monotherapies. Western blot analysis of breast cancer cells treated with TrkA and/or JAK2 inhibitors showed that co-inhibition of these two kinases significantly reduces levels of p-STAT3 (Y705), as well as stemness markers SOX2, MYC, and CD44. Taken together, these findings suggest that TrkA cooperates with the JAK2-STAT3 signaling pathway to promote breast cancer stem cells through increasing expression of SOX2, c-MYC, and CD44, and that co-inhibition of TrkA and JAK2 significantly suppressed breast cancer stemness, suggesting its future utility as a promising new treatment modality for patients with HER2-enriched breast cancers and triple-negative breast cancers.

Citation Format: Angelina T. Regua, Dongqin Zhu, Daniel L. Doheny, Grace L. Wong, Sara G. Manore, Calvin J. Wagner, Austin Arrigo, Mariana Najjar, Hui-Wen Lo. TrkA and JAK2-STAT3 pathway crosstalk promotes breast cancer stem cells 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 1039.