Targeting p53 as a promising therapeutic option for cancer by re-activating the wt or mutant p53's tumor suppression.

p53 protein, a product of the TP53 tumor suppressor gene, controls the cellular genome's integrity and is an important regulator of cell cycling, proliferation, apoptosis and metabolism. Mutations of TP53 or inactivation of its gene product are among the first events initiating malignant transformation. The consequent loss of control over the cell cycle, resulting in accelerated cell proliferation and facilitating metabolic reprogramming, gives the initiated (premalignant) cells numerous advantages over healthy cells.

Why (multi)targeting of cyclin-dependent kinases is a promising therapeutic option for hormone-positive breast cancer and beyond.

Estrogens, via induction of their specific receptors (e.g., ER-α), regulate cell proliferation, differentiation and morphogenesis in mammary epithelium.

Differential Potential of Pharmacological PARP Inhibitors for Inhibiting Cell Proliferation and Inducing Apoptosis in Human Breast Cancer Cells.

BRCA1/2-mutant cells are hypersensitive to inactivation of poly(ADP-ribose) polymerase 1 (PARP-1). We recently showed that inhibition of PARP-1 by NU1025 is strongly cytotoxic for BRCA1-positive BT-20 cells, but not BRCA1-deficient SKBr-3 cells. These results raised the possibility that other PARP-1 inhibitors, particularly those tested in clinical trials, may be more efficacious against BRCA1-deficient SKBr-3 breast cancer cells than NU1025.

Interactions Between Ataxia Telangiectasia Mutated Kinase Inhibition, Poly(ADP-ribose) Polymerase-1 Inhibition and BRCA1 Status in Breast Cancer Cells.

Background: Cells harboring BRCA1/BRCA2 mutations are hypersensitive to inhibition of poly(ADP-ribose) polymerase-1 (PARP-1). We recently showed that interference with PARP-1 activity by NU1025 is strongly cytotoxic for BRCA1-positive BT-20 cells but not BRCA1-deficient SKBr-3 cells. These unexpected observations prompted speculation that other PARP-1 inhibitor(s) may be more cytotoxic towards SKBr-3 cells.

PARP inhibition potentiates the cytotoxic activity of C-1305, a selective inhibitor of topoisomerase II, in human BRCA1-positive breast cancer cells.

Two cellular proteins encoded by the breast and ovarian cancer type 1 susceptibility (BRCA1 and BRCA2) tumor suppressor genes are essential for DNA integrity and the maintenance of genomic stability. Approximately 5-10% of breast and ovarian cancers result from inherited alterations or mutations in these genes. Remarkably, BRCA1/BRCA2-deficient cells are hypersensitive to selective inhibition of poly(ADP-ribose)polymerase 1 (PARP-1), whose primary functions are related to DNA base excision repair; PARP-1 inhibition significantly potentiates the cytotoxicity of various anti-cancer drugs, including inhibitors of topoisomerase I and II.