p66ShcA promotes malignant breast cancer phenotypes by alleviating energetic and oxidative stress.

Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumors and/or increase metastatic ability. During tumor development and progression to metastatic disease, physiological and pharmacological selective pressures influence parallel adaptive strategies within cancer cell sub-populations. Such adaptations allow cancer cells to withstand these stressful microenvironments. This Darwinian model of stress adaptation often prevents durable clinical responses and influences the emergence of aggressive cancers with increased metastatic fitness. However, the mechanisms contributing to such adaptive stress responses are poorly understood. We now demonstrate that the p66ShcA redox protein, itself a ROS inducer, is essential for survival in response to physiological stressors, including anchorage independence and nutrient deprivation, in the context of poor outcome breast cancers. Mechanistically, we show that p66ShcA promotes both glucose and glutamine metabolic reprogramming in breast cancer cells, to increase their capacity to engage catabolic metabolism and support glutathione synthesis. In doing so, chronic p66ShcA exposure contributes to adaptive stress responses, providing breast cancer cells with sufficient ATP and redox balance needed to withstand such transient stressed states. Our studies demonstrate that p66ShcA functionally contributes to the maintenance of aggressive phenotypes and the emergence of metastatic disease by forcing breast tumors to adapt to chronic and moderately elevated levels of oxidative stress.

Textural Characteristics of Biopsy-proven Metastatic Axillary Nodes on Preoperative Breast MRI in Breast Cancer Patients: A Feasibility Study.

OBJECTIVE: To determine the diagnostic accuracy of MRI textural analysis (TA) to differentiate malignant from benign axillary lymph nodes in patients with breast cancer. METHODS: This was an institutional review board-approved retrospective study of axillary lymph nodes in women with breast cancer that underwent ultrasound-guided biopsy and contrast-enhanced (CE) breast MRI from January 2015 to December 2018. TA of axillary lymph nodes was performed on 3D dynamic CE T1-weighted fat-suppressed, 3D delayed CE T1-weighted fat-suppressed, and T2-weighted fat-suppressed MRI sequences. Quantitative parameters used to measure TA were compared with pathologic diagnoses. Areas under the curve (AUC) were calculated using receiver operating characteristic curve analysis to distinguish between malignant and benign lymph nodes. RESULTS: Twenty-three biopsy-proven malignant lymph nodes and 24 benign lymph nodes were analyzed. The delayed CE T1-weighted fat-suppressed sequence had the greatest ability to differentiate malignant from benign outcome at all spatial scaling factors, with the highest AUC (0.84-0.93), sensitivity (0.78 [18/23] to 0.87 [20/23]), and specificity (0.76 [18/24] to 0.88 [21/24]). Kurtosis on the 3D delayed CE T1-weighted fat-suppressed sequence was the most prominent TA parameter differentiating malignant from benign lymph nodes (P < 0.0001). CONCLUSION: This study suggests that MRI TA could be helpful in distinguishing malignant from benign axillary lymph nodes. Kurtosis has the greatest potential on 3D delayed CE T1-weighted fat-suppressed sequences to distinguish malignant and benign lymph nodes.