Distinct Effects of Physiological and Supra-Physiologıcal Insulin on Docetaxel-Induced Apoptosis in TNBC

Objective: Triple-Negative Breast Cancer (TNBC) is characterized by aggressive behavior and reliance on taxanes like Docetaxel. Although hyperinsulinemia is linked to poor prognosis, the transcriptional mechanisms by which physiological versus supra-physiological insulin levels modulate taxane-induced stress remain poorly defined.Materials and Methods: MDA-MB-231 cells were treated with Docetaxel (5nM) alone or combined with physiological (5 ng/mL) and supra-physiological (19 ng/mL) insulin. Expression of survival (AKT1, MAPK1), apoptotic (CASP8, CASP9) and cell cycle (CDKN1A, CDKN1C) markers was analyzed using quantitative Real-Time PCR.Results: Docetaxel monotherapy triggered transcriptional changes consistent with mitotic arrest and apoptosis, as indicated by the upregulation of CDKN1A, CDKN1C and executioner caspases. Insulin co-treatment significantly attenuated this cytotoxic response. Notably, a non-linear dose response emerged: while MAPK1 signaling increased linearly with insulin concentration, the suppression of apoptotic and cell cycle arrest markers was most potent at physiological levels. Reduced suppression at supra-physiological doses suggests the activation of negative feedback loops.Conclusion: Insulin co-treatment induces a transcriptional profile consistent with reduced docetaxel sensitivity, characterized by sustained proliferative signaling and attenuation of apoptotic and cell cycle arrest responses at the transcriptional level. Importantly, even low-dose insulin was sufficient to attenuate pro-apoptotic transcriptional responses, suggesting that the tumor microenvironment may modulate chemotherapy efficacy independent of systemic metabolic syndrome. These findings suggest the insulin signaling axis as a potential modulator of chemotherapy response in TNBC.