No abstract

Purpose Women with early-onset (age ≤40) breast cancer are at high risk of carrying deleterious mutations in the BRCA1/2 genes; genetic assessment is thus recommended. Knowledge of BRCA1/2 mutation status is useful in guiding treatment decisions. To date, there has been no national study of BRCA1/2 testing among newly diagnosed women. Methods We used administrative data (2004–2007) from a national sample of 14.4 million commercially-insured patients to identify newly-diagnosed, early-onset breast cancer cases among women ages 20–40 (n=1,474). Cox models assessed BRCA1/2 testing, adjusting for covariates and differential lengths of follow-up. Results Overall, 30% of women age ≤40 received BRCA1/2 testing. In adjusted analyses, women of Jewish ethnicity were significantly more likely to be tested (HR=2.83, 95% CI 1.52–5.28), while black women (HR=0.34, 95% 0.18–0.64) and Hispanic women (HR=0.52, 95% CI 0.33–0.81) were significantly less likely to be tested than non-Jewish white women. Those enrolled in an HMO (HR=0.73, 95% CI 0.54–0.99) were significantly less likely to receive BRCA1/2 testing than those POS insurance plans. Testing rates rose sharply for women diagnosed in 2007 compared to 2004. Conclusions In this national sample of newly diagnosed breast cancer patients at high risk for BRCA1/2 mutations, genetic assessment was low, with marked racial differences in testing.

Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-beta) and/or modulate effects of TGF-beta in normal responses. Inhibition of TGF-beta signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-beta signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride (SB-505124), a member of a new class of small molecule inhibitors related to imidazole inhibitors of p38, which inhibit the TGF-beta type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. We demonstrate that this compound selectively and concentration-dependently inhibits ALK4-, ALK5-, and ALK 7-dependent activation of downstream cytoplasmic signal transducers, Smad2 and Smad3, and of TGF-beta-induced mitogen-activated protein kinase pathway components but does not alter ALK1, ALK2, ALK3 or ALK6-induced Smad signaling. SB-505124 also blocks more complex endpoints of TGF-beta action, as evidenced by its ability to abrogate cell death caused by TGF-beta1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542.

We used 2D-cocultures employing fibroblasts of different genetic backgrounds and MCF10A-derived human breast epithelial cells of increasingly malignant potential to investigate tumor-stroma interactions in breast cancer and to identify possible signaling pathways involved. Tumor cells induced expression of matrix-metalloproteinase 9 (MMP-9) in fibroblasts in a pattern dependent on the degree of their malignancy. In-situ zymography localized the main gelatinolytic activity around stromal cells in cocultures and xenografted tumors. Use of Smad3 knockout fibroblasts, small molecule inhibitors, and neutralizing antibodies showed that MMP-9 expression was induced by tumor cell-derived TNF-α and TGF-β, dependent on Smad-, Ras-, and PI3-kinase-signaling, and likewise modulated by subsequent HGF- and EGF-signaling. Together, our results indicate that MMP-9 levels in tumor fibroblasts are regulated by a complex tumor-stroma cross-talk, involving multiple ligands and cellular signaling pathways.