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 SEPT9_i1 promoting migration, epithelial-mesenchymal transition and paclitaxel resistance whereas SEPT9_i2 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 SEPT9_i2 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 SEPT9_i1 mRNA in their tumors than non-responders. Furthermore, majority of tumors that did not respond fully to taxanes in neoadjuvant settings had increased SEPT9_i1 mRNA expression in the residual tumor after treatment. Finally, we validated a SEPT9_i1 specific antibody for immunohistochemistry and SEPT9_i1 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.