Project description:The contralateral unaffected breast of women with unilateral breast cancer (cases) is a good model for defining subtype-specific risk since women with ER-negative index primaries are at high risk for subsequent ER-negative primary cancers. We performed random fine needle aspiration (rFNA) of the unaffected breasts of cases; samples from 30 subjects (15 ER-positive and 15 ER-negative cases matched for age, race and menopausal status), were used for Illumina expression array analysis. In this study, we have examined gene expression profiles in random fine needle aspirate (rFNA) samples from the contralateral breasts of women with new unilateral breast cancer (cases) to seek candidate panels of ER-specific risk biomarkers. On a discovery set of 30 women, we have identified gene expression differences in the contralateral breast that associate with ER+ or ER- index primary tumors.
Project description:The contralateral unaffected breast of women with unilateral breast cancer (cases) is a good model for defining subtype-specific risk since women with ER-negative index primaries are at high risk for subsequent ER-negative primary cancers. We performed random fine needle aspiration (rFNA) of the unaffected breasts of cases; samples from 30 subjects (15 ER-positive and 15 ER-negative cases matched for age, race and menopausal status), were used for Illumina expression array analysis.
Project description:CDK4/6 inhibition is the standard of care for estrogen receptor positive (ER+) breast cancer, although cytostasis is frequently observed, and new treatment strategies that enhance efficacy are required. We performed a genome-wide CRISPR screen to identify genetic determinants of CDK4/6 inhibitors sensitivity. Multiple genes involved in oxidative stress and ferroptosis modulated palbociclib sensitivity. Depletion or inhibition of GPX4 increased sensitivity to palbociclib in ER+ breast cancer models, and sensitised triple negative breast cancer models to palbociclib, with GPX4 null xenografts being highly sensitive to palbociclib. Palbociclib induced oxidative stress and disordered lipid metabolism with lipid peroxidation, leading to a ferroptosis-sensitive state. Lipid peroxidation relied on a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 inhibition creates vulnerability to ferroptosis that could be exploited through combination with GPX4 inhibitors, enhancing sensitivity to CDK4/6 inhibition in breast cancer.
Project description:Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.
Project description:Under conditions of hormonal adjuvant treatment the estrogen receptor apoprotein supports breast cancer cell cycling through the retinoic acid receptor α1 apoprotein. Basal proliferation persisted in estrogen-sensitive breast cancer cells grown in hormone depleted conditioned media without or with 4-hydroxytamoxifen (OH-Tam). Downregulating ER using siRNA inhibited basal proliferation by promoting cell cycle arrest. The basal expression of RARα1, the only RARα isoform that was expressed in breast cancer cell lines and in most breast tumors, was supported by apo-ER but was unaffected by OH-Tam. The overlapping tamoxifen-insensitive gene regulation by apo-ER and apo-RARα1 comprised activation of mainly genes promoting cell cycle and mitosis and suppression of genes involved in growth inhibition.
Project description:Expression levels of proteins and phosphoproteins, covering major cancer signaling pathways with a special focus on breast cancer biology, were obtained for a series of 164 breast cancer tumor specimens with positive estrogen receptor status.
