Abstract Microtubule-targeting agents (MTAs), including the taxane paclitaxel, are widely used for the treatment of breast cancer. However, there are no clinically validated biomarkers to predict taxane response. Emerging evidence implicates septins, a conserved family of GTP-binding cytoskeletal proteins, key regulators of growth, migration, invasion, and taxane response of breast cancer cells in vitro. Notably, isoforms of septin9 (SEPT9) have opposing roles with SEPT9ᵢ1 promoting migration, epithelial-mesenchymal transition and paclitaxel resistance whereas SEPT9ᵢ2 is associated with decreased oncogenic phenotypes and may serve a protective role. We tested the hypothesis that septin9 isoform expression in breast tumors correlates with the response of breast cancer patients to taxane chemotherapy regimens in both retrospective and prospective clinical studies. In a retrospective analysis we found a significant increase in post-metastatic survival time of taxane-treated patients whose tumors expressed the highest levels of SEPT9ᵢ2 mRNA. Notably, this correlation was only observed in women diagnosed with triple-negative breast cancer (TNBC) that rely most heavily on response to taxanes as they are not co-administered with targeted therapeutics. In a prospective study of neoadjuvant taxane response, women with a complete pathological response to taxane-based chemotherapy regimens had significantly lower expression of SEPT9ᵢ1 mRNA in their tumors than non-responders. Furthermore, majority of tumors that did not respond fully to taxanes in neoadjuvant settings had increased SEPT9ᵢ1 mRNA expression in the residual tumor after treatment. Finally, we validated a SEPT9ᵢ1 specific antibody for immunohistochemistry and SEPT9ᵢ1 mRNA correlated with protein in breast biopsies. Ongoing experiments in the laboratory are elucidating the mechanism by which expression of septin9 isoforms regulates response to taxane chemotherapy using isogenic cell line and tumor models. This work is uncovering a reciprocal relationship between expression of oncogenic and tumor suppressive isoforms and identifying alternative chemotherapeutic options for treatment of tumors with unfavorable septin expression profiles. Citation Format: Jycole E. Bush, Jacob Essif, KATE LATHROP, April Risinger. Septin9 isoforms as biomarkers of taxane response in breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (7 Suppl): Abstract nr 3735.
Bush et al. (Fri,) studied this question.