| First Author | George JW | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 13 | Pages | 3445-3450 |
| PubMed ID | 28289208 | Mgi Jnum | J:318881 |
| Mgi Id | MGI:6863322 | Doi | 10.1073/pnas.1612284114 |
| Citation | George JW, et al. (2017) Specific deletion of LKB1/Stk11 in the Mullerian duct mesenchyme drives hyperplasia of the periurethral stroma and tumorigenesis in male mice. Proc Natl Acad Sci U S A 114(13):3445-3450 |
| abstractText | Nearly all older men will experience lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH), the etiology of which is not well understood. We have generated Stk11(CKO) mice by conditional deletion of the liver kinase B1 (LKB1) tumor suppressor gene, Stk11 (serine threonine kinase 11), in the fetal Mullerian duct mesenchyme (MDM), the caudal remnant of which is thought to be assimilated by the urogenital sinus primordial mesenchyme in males during fetal development. We show that MDM cells contribute to the postnatal stromal cells at the dorsal aspect of the prostatic urethra by lineage tracing. The Stk11(CKO) mice develop prostatic hyperplasia with bladder outlet obstruction, most likely because of stromal expansion. The stromal areas from prostates of Stk11(CKO) mice, with or without significant expansion, were estrogen receptor positive, which is consistent with both MD mesenchyme-derived cells and the purported importance of estrogen receptors in BPH development and/or progression. In some cases, stromal hyperplasia was admixed with epithelial metaplasia, sometimes with keratin pearls, consistent with squamous cell carcinomas. Mice with conditional deletion of both Stk11 and Pten developed similar features as the Stk11(CKO) mice, but at a highly accelerated rate, often within the first few months after birth. Western blot analyses showed that the loss of LKB1 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) induces activation of the phospho-5' adenosine monophosphate-activated protein kinase and phospho-AKT serine/threonine kinase 1 signaling pathways, as well as increased total and active beta-catenin. These results suggest that activation of these signaling pathways can induce hyperplasia of the MD stroma, which could play a significant role in the etiology of human BPH. |
