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Chemoresistance is a primary cause of breast cancer treatment failure, and protein-protein interactions significantly contribute to chemoresistance during different stages of breast cancer progression. In pursuit of novel biomarkers and relevant protein-protein interactions occurring during the emergence of breast cancer chemoresistance, we used a computational predictive biological (CPB) approach. CPB identified associations of adhesion molecules with proteins connected with different breast cancer proteins associated with chemoresistance. This approach identified an association of Integrin β1 (ITGB1) with chemoresistance and breast cancer stem cell markers. ITGB1 activated the Focal Adhesion Kinase (FAK) pathway promoting invasion, migration, and chemoresistance in breast cancer by upregulating Erk phosphorylation. FAK also activated Wnt/Sox2 signaling, which enhanced self-renewal in breast cancer. Activation of the FAK pathway by ITGB1 represents a novel mechanism linked to breast cancer chemoresistance, which may lead to novel therapies capable of blocking breast cancer progression by intervening in ITGB1-regulated signaling pathways. [Display omitted] • Developed a novel Computational-Predictive-Biological (CPB) strategy to predict different types of biomarkers in cancers. • CBP identified that ITGB1 is associated with chemoresistance, and cancer stem cell associated proteins in breast cancer. • ITGB1 regulated chemoresistance via activation of FAK pathway which regulates survival pathways, invasion, migration. • ITGB1 also regulated activated Wnt/Sox2 signaling through FAK, which enhanced self-renewal in breast cancer. • Thus, CBP established a unified pathway to regulate chemoresistance in breast cancer and ITGB1 as a potential biomarker. [ABSTRACT FROM AUTHOR]

Autophagy can either be cytoprotective or promote cell death in a context-dependent manner in response to stress. How autophagy leads to autophagy dependent cell death requires further clarification. In this study, we document a nonlinear roller coaster form of autophagy oscillation when cells are subjected to different stress conditions. Serum starvation induces an initial primary autophagic peak at 6 h, that helps to replenish cells with de novo fluxed nutrients, but protracted stress lead to a secondary autophagic peak around 48 h. Time kinetic studies indicate that the primary autophagic peak is reversible, whereas the secondary autophagic peak is irreversible and leads to cell death. Key players involved in different stages of autophagy including initiation, elongation and degradation during this oscillatory sequence were identified. A similar molecular pattern was intensified under apoptosis-deficient conditions. mTOR was the central molecule regulating this autophagic activity, and upon knockdown a steady increase of autophagy without any non-linear fluctuation was evident. An unbiased proteome screening approach was employed to identify the autophagy molecules potentially regulating these autophagic peaks. Our proteomics analysis has identified Annexin A2 as a stress-induced protein to implicate in autophagy fluctuation and its deficiency reduced autophagy. Moreover, we report that mTOR in its phosphorylated condition interacts with Annexin A2 to induce autophagy fluctuation by altering its cellular localization. The work highlights the molecular mechanism of a mTOR-dependent roller coaster fluctuation of autophagy and autophagy dependent cell death during prolong stress. • Stress creates a roller coaster form of biphasic autophagic fluctuation. • Stress beyond point of no return leads to autophagy dependent cell death. • Autophagic point of no return is modulated by mTOR. • mTOR-Annexin A2 plays significant role in autophagic point of no return. [ABSTRACT FROM AUTHOR]