Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis.

Cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and polyubiquitination by SCF(FBX4-alphaB crystallin). Inhibition of cyclin D1 proteolysis has been implicated as a causative factor leading to its overexpression in breast and esophageal carcinomas; however, the contribution of stable cyclin D1 to the genesis of such carcinomas has not been evaluated. We therefore generated transgenic mice wherein expression of either wild-type or a stable cyclin D1 allele (D1T286A) is regulated by MMTV-LTR. MMTV-D1T286A mice developed mammary adenocarcinomas at an increased rate relative to MMTV-D1 mice. Similar to human cancers that overexpress cyclin D1, D1T286A tumors were estrogen receptor-positive and exhibited estrogen-dependent growth. Collectively, these results suggest that temporal control of cyclin D1 subcellular localization and proteolysis is critical for maintenance of homeostasis within the mammary epithelium.