TY - JOUR
T1 - LGR6-dependent conditional inactivation of E-cadherin and p53 leads to invasive skin and mammary carcinomas in mice
AU - Ter Steege, Eline J
AU - Sijnesael, Thijmen
AU - Enserink, Lotte
AU - Klarenbeek, Sjoerd
AU - Haakma, Wisse E
AU - Bakker, Elvira R M
AU - Derksen, Patrick W B
N1 - Funding Information:
We would like to acknowledge the UMC Utrecht Pathology Tissue Facility for histology support. We are also grateful for the support of the Utrecht University animal facility, Gemeenschappelijk Dieren Laboratorium (GDL). This work was supported by grants from the Dutch Research Counsel-Talent Scheme VENI (NWO/ZonMW VENI 016.186.138), the Dutch Cancer Society (KWF Young Investigator Grant 10957, KWF-UU-2016-10456), and the European Union's Horizon 2020 FET Proactive program under the grant agreement No. 731957 (MECHANO-CONTROL). This publication is also partially based upon work from COST action LOBSTERPOT (CA19138), supported by COST (European Cooperation in Science and Technology).
Funding Information:
We would like to acknowledge the UMC Utrecht Pathology Tissue Facility for histology support. We are also grateful for the support of the Utrecht University animal facility, Gemeenschappelijk Dieren Laboratorium (GDL). This work was supported by grants from the Dutch Research Counsel-Talent Scheme VENI (NWO/ZonMW VENI 016.186.138), the Dutch Cancer Society (KWF Young Investigator Grant 10957, KWF-UU-2016-10456), and the European Union's Horizon 2020 FET Proactive program under the grant agreement No. 731957 (MECHANO-CONTROL). This publication is also partially based upon work from COST action LOBSTERPOT (CA19138), supported by COST (European Cooperation in Science and Technology).
Publisher Copyright:
© 2022
PY - 2023/1
Y1 - 2023/1
N2 - Tissue-specific inactivation of E-cadherin combined with tumor suppressor loss leads to invasive and metastatic cancers in mice. While epidermal E-cadherin loss in mice induces squamous cell carcinomas, inactivation of E-cadherin in the mammary gland leads to invasive lobular carcinoma. To further explore the carcinogenic consequences of cell-cell adhesion loss in these compartments, we developed a new conditional mouse model inactivating E-cadherin (Cdh1) and p53 (Trp53) simultaneously in cells expressing the leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6), a putative epithelial stem cell marker in the skin and alveolar progenitor marker in the mammary gland. Compound Lgr6-CreERT2;Cdh1F;Trp53F female mice containing either heterozygous or homozygous Cdh1F alleles were bred, and Lgr6-driven Cre expression was activated in pre-puberal mice using tamoxifen. We observed that 41% of the mice (16/39) developed mostly invasive squamous-type skin carcinomas, but also a non-lobular mammary tumor was formed. In contrast to previous K14cre or WAPcre E-cadherin and p53 compound models, no significant differences were detected in the tumor-free survival of Lgr6-CreERT2 heterozygous Cdh1F/WT;Trp53F/F versus homozygous Cdh1F/F;Trp53F/F mice (778 versus 754 days, p=0.5). One Cdh1F homozygous mouse presented with lung metastasis that originated from a non-lobular and ERα negative invasive mammary gland carcinoma with squamous metaplasia. In total, 2/8 (25%) Cdh1F heterozygous and 3/12 (25%) Cdh1F homozygous mice developed metastases to lungs, liver, lymph nodes, or the gastro-intestinal tract. In conclusion, we show that inducible and conditional Lgr6-driven inactivation of E-cadherin and p53 in mice causes squamous cell carcinomas of the skin in approximately 40% of the mice and an occasional ductal-type mammary carcinoma after long latency periods.
AB - Tissue-specific inactivation of E-cadherin combined with tumor suppressor loss leads to invasive and metastatic cancers in mice. While epidermal E-cadherin loss in mice induces squamous cell carcinomas, inactivation of E-cadherin in the mammary gland leads to invasive lobular carcinoma. To further explore the carcinogenic consequences of cell-cell adhesion loss in these compartments, we developed a new conditional mouse model inactivating E-cadherin (Cdh1) and p53 (Trp53) simultaneously in cells expressing the leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6), a putative epithelial stem cell marker in the skin and alveolar progenitor marker in the mammary gland. Compound Lgr6-CreERT2;Cdh1F;Trp53F female mice containing either heterozygous or homozygous Cdh1F alleles were bred, and Lgr6-driven Cre expression was activated in pre-puberal mice using tamoxifen. We observed that 41% of the mice (16/39) developed mostly invasive squamous-type skin carcinomas, but also a non-lobular mammary tumor was formed. In contrast to previous K14cre or WAPcre E-cadherin and p53 compound models, no significant differences were detected in the tumor-free survival of Lgr6-CreERT2 heterozygous Cdh1F/WT;Trp53F/F versus homozygous Cdh1F/F;Trp53F/F mice (778 versus 754 days, p=0.5). One Cdh1F homozygous mouse presented with lung metastasis that originated from a non-lobular and ERα negative invasive mammary gland carcinoma with squamous metaplasia. In total, 2/8 (25%) Cdh1F heterozygous and 3/12 (25%) Cdh1F homozygous mice developed metastases to lungs, liver, lymph nodes, or the gastro-intestinal tract. In conclusion, we show that inducible and conditional Lgr6-driven inactivation of E-cadherin and p53 in mice causes squamous cell carcinomas of the skin in approximately 40% of the mice and an occasional ductal-type mammary carcinoma after long latency periods.
KW - Animals
KW - Breast Neoplasms/metabolism
KW - Cadherins/genetics
KW - Carcinoma, Ductal, Breast
KW - Carcinoma, Squamous Cell
KW - Female
KW - Mice
KW - Receptors, G-Protein-Coupled/genetics
KW - Tumor Suppressor Protein p53/genetics
KW - Squamous cell carcinoma
KW - Breast cancer
KW - E-cadherin
KW - Skin
KW - Lgr6
UR - http://www.scopus.com/inward/record.url?scp=85141521643&partnerID=8YFLogxK
U2 - 10.1016/j.neo.2022.100844
DO - 10.1016/j.neo.2022.100844
M3 - Article
C2 - 36371908
SN - 1522-8002
VL - 35
JO - Neoplasia
JF - Neoplasia
M1 - 100844
ER -