Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis.
Metastatic disease is the primary cause of death in breast cancer, the most common malignancy in Western women. Loss of E-cadherin is associated with tumor metastasis, as well as with invasive lobular carcinoma (ILC), which accounts for 10%-15% of all breast cancers. To study the role of E-cadherin in breast oncogenesis, we have introduced conditional E-cadherin mutations into a mouse tumor model based on epithelium-specific knockout of p53. Combined loss of E-cadherin and p53 resulted in accelerated development of invasive and metastatic mammary carcinomas, which show strong resemblance to human ILC. Moreover, loss of E-cadherin induced anoikis resistance and facilitated angiogenesis, thus promoting metastatic disease. Our results suggest that loss of E-cadherin contributes to both mammary tumor initiation and metastasis.
Derksen
Patrick W B
PW
Division of Molecular Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Liu
Xiaoling
X
Saridin
Francis
F
van der Gulden
Hanneke
H
Zevenhoven
John
J
Evers
Bastiaan
B
van Beijnum
Judy R
JR
Griffioen
Arjan W
AW
Vink
Jacqueline
J
Krimpenfort
Paul
P
Peterse
Johannes L
JL
Cardiff
Robert D
RD
Berns
Anton
A
Jonkers
Jos
J
D000818:Animals; D023102:Anoikis / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D018275:Carcinoma, Lobular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D042361:Mammary Glands, Human / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D016159:Tumor Suppressor Protein p53