Although the signaling pathways controlling muscle regeneration are fairly well known, how these signals lead to altered chromatin structure remains undiscovered. A group of scientists at the Burnham Institute for Medical Research in La Jolla, CA, analyzed the mechanism by which certain cellular signaling cues cause epigenetic modifications when released within the regenerative microenvironment, thus controlling the expression of genes that regulate growth and differentiation of muscle stem cells that repair injured muscle.

In a recent publication in Molecular Cell, the scientific group, led by Pier Lorenzo Puri, MD, Ph.D., shows how two signaling pathways, PI3K/AKT and p38, work together to assemble components of the protein complexes responsible for muscle-specific transcription, and how each pathway is responsible for a distinct step in the transcription process. Additionally, the team was able to pharmacologically separate these two steps, showing that selective interference with either cascade leads to incomplete assembly of protein complexes, thus preventing muscle-specific gene expression. The results point to possible pharmacological avenues for selective control of gene expression in adult muscle stem cells that may have therapeutic potential in regenerative medicine.

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These kinds of mutations that break tumor suppressors in half may turn out to be common in many kinds of carcinomas, particularly those with deficiencies in DNA repair pathways similar to BRCA1, a question that only a systematic search can answer, said Dr. Saal.

Similar research is underway in tumors from carriers of germline mutations in BRCA2, the other known major breast cancer susceptibility gene, said Dr. Borg. BRCA2 has a role downstream in the same DNA double strand break repair pathway as BRCA1, but tumors from BRCA2 mutation carriers have a quite different phenotype compared to BRCA1 tumors, less often involving PTEN loss. However, like BRCA1, BRCA2 tumors have an instable genome with massive chromosomal aberrations, suggesting that other genes may be targeted.

Basal-like breast cancer tumors, whether caused by BRCA1 mutations or of the non-hereditary type, are among the most aggressive tumors “ they grow fast and spread quickly, making them more likely than other types of cancer to be fatal. These tumors are more likely to be resistant to standard breast cancer treatments, such as Tamoxifen or Herceptin, making them especially difficult to treat. As a result, many young BRCA1 carriers opt to have their breasts prophylactically removed instead of waiting for cancer to appear.

Breast cancers caused by BRCA1 mutations tend to affect women much earlier “ often before menopause and sometimes in their 20s and 30s “ and between 60 and 80 percent of women who carry a BRCA1 mutation will develop breast cancer at some point during their lives. BRCA1 mutation carriers are most common among African-American women and women of Ashkenazi Jewish descent. Inherited BRCA1 (and BRCA2) mutations also predispose women to ovarian cancer, a disease that frequently escape early diagnosis and which has a fatal outcome in advanced stages.

Additional Columbia researchers involved in the study include Hanina Hibshoosh, M.D., associate professor of clinical pathology and Vundavalli Murty, M.D., associate professor of pathology, and others.

Identifying these rearrangements would not have been possible without the support of the shared resources of the Herbert Irving Comprehensive Cancer Center and our collaboration with Drs. Borg, Saal, Hibshoosh and Murty, said Dr. Parsons.

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