This study investigates the metabolic defects caused by loss of matrix attachment in mammary epithelial cells and how antioxidant and oncogene treatments can rescue these defects. The research shows that when mammary epithelial cells detach from their extracellular matrix (ECM), they experience an ATP deficiency due to impaired glucose transport. Overexpression of the oncogene ErbB2 rescues this ATP deficiency by stabilizing the EGFR and activating the PI(3)K pathway, which enhances glucose uptake. This rescue is dependent on the pentose phosphate pathway (PPP), which generates NADPH and helps maintain redox balance. Interestingly, antioxidant treatment alone can also rescue the ATP deficiency, which is achieved through the stimulation of fatty acid oxidation (FAO), a process that is inhibited by reactive oxygen species (ROS) generated during ECM detachment. The study also demonstrates that antioxidants promote the survival of matrix-deprived cells and enhance their ability to form anchorage-independent colonies. These findings highlight the importance of matrix attachment in regulating metabolic activity and reveal an unexpected mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation. The research further shows that ROS accumulation in matrix-deprived cells is linked to increased oxidative stress, and that antioxidants can reduce ROS levels, thereby promoting cell survival. Additionally, the study suggests that antioxidants may have dual roles in tumorigenesis, potentially suppressing tumor growth by preventing oxidative damage to DNA while also promoting tumor growth by allowing survival of cells in altered matrix environments. The findings have implications for understanding the metabolic adaptations required for cancer progression and the potential therapeutic use of antioxidants in cancer treatment.This study investigates the metabolic defects caused by loss of matrix attachment in mammary epithelial cells and how antioxidant and oncogene treatments can rescue these defects. The research shows that when mammary epithelial cells detach from their extracellular matrix (ECM), they experience an ATP deficiency due to impaired glucose transport. Overexpression of the oncogene ErbB2 rescues this ATP deficiency by stabilizing the EGFR and activating the PI(3)K pathway, which enhances glucose uptake. This rescue is dependent on the pentose phosphate pathway (PPP), which generates NADPH and helps maintain redox balance. Interestingly, antioxidant treatment alone can also rescue the ATP deficiency, which is achieved through the stimulation of fatty acid oxidation (FAO), a process that is inhibited by reactive oxygen species (ROS) generated during ECM detachment. The study also demonstrates that antioxidants promote the survival of matrix-deprived cells and enhance their ability to form anchorage-independent colonies. These findings highlight the importance of matrix attachment in regulating metabolic activity and reveal an unexpected mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation. The research further shows that ROS accumulation in matrix-deprived cells is linked to increased oxidative stress, and that antioxidants can reduce ROS levels, thereby promoting cell survival. Additionally, the study suggests that antioxidants may have dual roles in tumorigenesis, potentially suppressing tumor growth by preventing oxidative damage to DNA while also promoting tumor growth by allowing survival of cells in altered matrix environments. The findings have implications for understanding the metabolic adaptations required for cancer progression and the potential therapeutic use of antioxidants in cancer treatment.