Nuclear Factor-KB (NF-KB) regulates proliferation and branching in mouse mammary epithelium

The nuclear factor-kappaB (NF-kappaB) family of transcription factors has b een shown to regulate proliferation in several cell types. Although recent studies have demonstrated aberrant expression or activity of NF-kappaB in h uman breast cancer cell lines and tumors, little is known regarding the pre cise role of NF-kappaB in normal proliferation and development of the mamma ry epithelium. We investigated the function of NF-kappaB during murine earl y postnatal mammary gland development by observing the consequences of incr eased NF-kappaB activity in mouse mammary epithelium lacking the gene encod ing I kappaB alpha, a major inhibitor of NF-kappaB. Mammary tissue containi ng epithelium from inhibitor kappaB alpha (I kappaB alpha)-deficient female donors was transplanted into the gland-free mammary stroma of wild-type mi ce, resulting in an increase in lateral ductal branching and pervasive intr aductal hyperplasia. A two- to threefold increase in epithelial cell number was observed in I kappaB alpha -deficient epithelium compared with control s. Epithelial cell proliferation was strikingly increased in I kappaB alpha -deficient epithelium, and no alteration in apoptosis was detected. The ex tracellular matrix adjacent to I kappaB alpha -deficient epithelium was red uced. Consistent with in vivo data, a fourfold increase in epithelial branc hing was also observed in purified I kappaB alpha -deficient primary epithe lial cells in three-dimensional culture. These data demonstrate that NF-kap paB positively regulates mammary epithelial proliferation, branching, and f unctions in maintenance of normal epithelial architecture during early post natal development.