Replacement of E-cadherin by N-cadherin in the mammary gland leads to fibrocystic changes and tumor formation.
BACKGROUND
E-cadherin (E-cad; cadherin 1) and N-cadherin (N-cad; cadherin 2) are the most prominent members of the cadherin family of cell adhesion molecules. Although they share many structural and functional features, they are expressed in an almost mutually exclusive manner in vivo.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Molecular Embryology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany.
Ahmed M
AM
Kotb
Andreas
A
Hierholzer
Rolf
R
Kemler
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D047688:Breast Cyst / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005348:Fibrocystic Breast Disease / Q000235:genetics / Q000473:pathology; D005355:Fibrosis / Q000235:genetics; D020868:Gene Silencing; D016158:Genes, p53; D007774:Lactation / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy
D015820:Cadherins; C489083:Cdh2 protein, mouse; D005346:Fibroblast Growth Factors