In addition, hypoxia enriches the number of BCSCs by upregulating pathways contributing to their stem-like proliferation and reduced apoptosis [143,144]. resistance is usually multi-faceted and entails multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the malignancy types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target important pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will spotlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drugCinhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome. and the genes encoding -tubulin IIA and III, increased 2C3-fold upon PTX TCPOBOP treatment but was decreased after miR-100 transfection . MAPs and other proteins involved in MT dynamics are important markers of MT-targeting drug resistance in breast malignancy . MAP4 stabilizes MTs by raising the rescue frequency and plays a role in mitotic MT dynamics, thereby causing PTX resistance [76,77]. Previous studies have shown that MAP4 is usually inversely regulated by p53, which resulted in enhanced MT polymerization and taxane sensitivity in the C127 mammary cell collection . Given this information, p53-mediated TCPOBOP downregulation of MAP4 may be a potential mechanism of taxane resistance. Tau is usually a MAP that enables tubulin polymerization and promotes MT stabilization . Preincubation of tubulin with tau protein reduces PTX binding and PTX-induced MT polymerization . Lowered tau expression could serve as a biomarker to determine which patients will benefit from PTX treatment, as it makes MTs more vulnerable to PTX and BC cells more sensitive to the drug. In addition, inhibiting tau function may be a useful therapeutic method to improve PTX response . The septin family of GTPases spatially guides the direction of MT plus-end movement through suppression of MT catastrophe . They also play an important scaffolding role in membrane compartmentalization and protection against protein degradation, emerging as potential mediators of chemoresistance and vital organizers of MAPs and cancer-associated signaling pathways . Overexpression of septins, particularly septin 9, in MDA-MB-231 cells increased PTX TCPOBOP resistance . This resistance was enhanced by long-chain tubulin polyglutamylation and linked to altered MT dynamics and early relocalization of septin filaments from actin fibers to MTs. Tubulin Binding Cofactor C (TBCC) is usually a protein responsible for proper folding of and -tubulin subunits into the MT . overexpression resulted in increased soluble, non-polymerizable tubulins and decreased soluble, polymerizable dimers and a slight decrease in the tubulin content of MTs. In human BC cells overexpressing TBCC, MT dynamicity was lowered, and cell cycle distribution was altered such that a higher proportion of these cells was in the G2-M phase and a lower proportion in the S phase. These TBCC overexpressing variants showed increased PTX sensitivity, potentially caused by lower levels of MT dynamicity and the increase in target cells (cells in G2-M) for anti-proliferative drugs [85,86]. 2.3.2. MT Regulators in Mitosis and Cell Cycle Progression Rabbit polyclonal to ATP5B Regulation of MT functions at the mitotic spindle are critical for functionality of the taxanes, and disruptions of these functions provide avenues for taxane resistance. NIMA-related Kinase 2 (NEK2) is usually a regulator of centrosome separation, which is a prerequisite for mitotic spindle assembly [87,88]. Both NEK2 and LIN9, the transcriptional regulator of NEK2, are elevated with taxane resistance in TNBC cells.