Specific deletion of LKB1/<i>Stk11</i> in the Müllerian duct mesenchyme drives hyperplasia of the periurethral stroma and tumorigenesis in male mice.

Abstract

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 <i>Stk11</i>^<i>CKO</i> mice by conditional deletion of the liver kinase B1 (LKB1) tumor suppressor gene, <i>Stk11</i> (serine threonine kinase 11)<i>,</i> in the fetal Müllerian 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 <i>Stk11</i>^<i>CKO</i> mice develop prostatic hyperplasia with bladder outlet obstruction, most likely because of stromal expansion. The stromal areas from prostates of <i>Stk11</i>^<i>CKO</i> 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 <i>Stk11</i> and <i>Pten</i> developed similar features as the <i>Stk11</i>^<i>CKO</i> 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 β-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.