GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma.

Cerebellar development requires regulated proliferation of cerebellar granule neuron progenitors (CGNPs). Inadequate CGNP proliferation causes cerebellar hypoplasia whereas excessive CGNP proliferation can cause medulloblastoma, the most common malignant pediatric brain tumor. Although sonic hedgehog (SHH) signaling is known to activate CGNP proliferation, the mechanisms downregulating proliferation are less defined. We investigated CGNP regulation by GSK-3, which downregulates proliferation in the forebrain, gut and breast by suppressing mitogenic WNT signaling in mouse. In striking contrast to these systems, we found that co-deleting Gsk3a and Gsk3b blocked CGNP proliferation, causing severe cerebellar hypoplasia. The GSK-3 inhibitor CHIR-98014 similarly downregulated SHH-driven proliferation. Transcriptomic analysis showed activated WNT signaling and upregulated Cdkn1a in Gsk3a/b-deleted CGNPs. Ctnnb co-deletion increased CGNP proliferation and rescued cerebellar hypoproliferation in Gsk3a/b mutants, demonstrating physiological control of CGNPs by GSK-3, mediated through WNT. SHH-driven medulloblastomas similarly required GSK-3, as co-deleting Gsk3a/b blocked tumor growth in medulloblastoma-prone SmoM2 mice. These data show that a GSK-3/WNT axis modulates the developmental proliferation of CGNPs and the pathological growth of SHH-driven medulloblastoma. The requirement for GSK-3 in SHH-driven proliferation suggests that GSK-3 may be targeted for SHH-driven medulloblastoma therapy.

Multiple mediation analysis of racial disparity in breast cancer survival.

BACKGROUND: Racial (Black vs. White) disparities in breast cancer survival have proven difficult to mitigate. Targeted strategies aimed at the primary factors driving the disparity offer the greatest potential for success. The purpose of this study was to use multiple mediation analysis to identify the most important mediators of the racial disparity in breast cancer survival. METHODS: This was a retrospective cohort study of non-Hispanic Black and non-Hispanic White women diagnosed with invasive breast cancer in Florida between 2004 and 2015. Cox regression was used to obtain unadjusted and adjusted hazard ratios (HR) with 95% confidence intervals (CI) for the association of race with 5- and 10-year breast cancer death. Multiple mediation analysis of tumor (advanced disease stage, tumor grade, hormone receptor status) and treatment-related factors (receipt of surgery, chemotherapy, radiotherapy, and hormone therapy) was used to determine the most important mediators of the survival disparity. RESULTS: The study population consisted of 101,872 women of whom 87.0% (n = 88,617) were White and 13.0% were Black (n = 13,255). Black women experienced 2.3 times (HR, 2.27; 95% CI, 2.16-2.38) the rate of 5-year breast cancer death over the follow-up period, which decreased to a 38% increased rate (HR, 1.38; 95% CI, 1.31-1.45) after adjustment for age and the mediators of interest. Combined, all examined mediators explained 73% of the racial disparity in 5-year breast cancer survival. The most important mediators were: (1) advanced disease stage (44.8%), (2) nonreceipt of surgery (34.2%), and (3) tumor grade (18.2%) and hormone receptor status (17.6%). Similar results were obtained for 10-year breast cancer death. CONCLUSION: These results suggest that additional efforts to increase uptake of screening mammography in hard-to-reach women, and, following diagnosis, access to and receipt of surgery may offer the greatest potential to reduce racial disparities in breast cancer survival for women in Florida.