Replacement of E-cadherin by N-cadherin in the mammary gland leads to fibrocystic changes and tumor formation

To explore functional differences between the two cadherins in vivo, we recently generated a knock-in line in which N-cad is expressed from the E-cad locus. In combination with a conditional gene inactivation approach, we expressed N-cad in the absence of E-cad (referred to as Ncadk.i.) in alveolar epithelial cells of the mammary gland starting in late pregnancy.We found that the sole presence of N-cad induces constitutively active fibroblast growth factor (Fgf) signaling and a precocious involution resulting in massive apoptosis of alveolar cells. To block apoptosis, we conditionally deleted one allele of p53 in Ncadk.i. mice and observed a temporal rescue of alveolar morphology and function. However, an accumulation of fibrotic tissue and cysts with increasing age and lactation cycles was observed. This phenotype closely resembled fibrocystic mastopathy (FM), a common disorder in humans, which is thought to precede breast cancer. Concordantly, 55% of Ncadk.i. mice harboring a heterozygous p53 deletion developed malignant and invasive tumors.Our results demonstrate a possible role for N-cad in the formation of fibrosis and cysts in the mammary gland. Moreover, we show that these lesions precede the development of malignant tumors. Thus, we provide a new mouse model to investigate the molecular mechanisms of fibrocystic mastopathy and the transition from benign to malignant tumors.Classical cadherins are cell adhesion molecules, which play fundamental roles in the development of multicellular organisms [1]. E-cadherin (E-cad, Cdh1) is the founding member of the cadherin gene family and is essential for the integrity of epithelial tissues. The first epithelial cell layer in the development of mouse embryos, the trophectoderm of blastocysts, requires E-cad for proper function. In later embryonic stages and in adult organisms, E-cad also provides adhesive strength to form polarized epithelial cell layers [2]. N-cadherin (N-cad, Cdh2) is initially expressed at the gastr