Reference SummaryTumiati M, Oncogene 2016 Jan 25;():
Title |
Rad51c- and Trp53-double-mutant mouse model reveals common features of homologous recombination-deficient breast cancers. |
Authors |
Tumiati M; Munne PM; Edgren H; Eldfors S; Hemmes A; Kuznetsov SG |
Journal |
Oncogene |
Volume |
|
Issue |
|
Year |
2016 |
Pages |
|
Abstract |
Almost half of all hereditary breast cancers (BCs) are associated with germ-line mutations in homologous recombination (HR) genes. However, the tumor phenotypes associated with different HR genes vary, making it difficult to define the role of HR in BC predisposition. To distinguish between HR-dependent and -independent features of BCs, we generated a mouse model in which an essential HR gene, Rad51c, is knocked-out specifically in epidermal tissues. Rad51c is one of the key mediators of HR and a well-known BC predisposition gene. Here, we demonstrate that deletion of Rad51c invariably requires inactivation of the Trp53 tumor suppressor (TP53 in humans) to produce mammary carcinomas in 63% of female mice. Nonetheless, loss of Rad51c shortens the latency of Trp53-deficient mouse tumors from 11 to 6 months. Remarkably, the histopathological features of Rad51c-deficient mammary carcinomas, such as expression of hormone receptors and luminal epithelial markers, faithfully recapitulate the histopathology of human RAD51C-mutated BCs. Similar to other BC models, Rad51c/p53 double-mutant mouse mammary tumors also reveal a propensity for genomic instability, but lack the focal amplification of the Met locus or distinct mutational signatures reported for other HR genes. Using the human mammary epithelial cell line MCF10A, we show that deletion of TP53 can rescue RAD51C-deficient cells from radiation-induced cellular senescence, whereas it exacerbates their centrosome amplification and nuclear abnormalities. Altogether, our data indicate that a trend for genomic instability and inactivation of Trp53 are common features of HR-mediated BCs, whereas histopathology and somatic mutation patterns are specific for different HR genes.Oncogene advance online publication, 25 January 2016; doi:10.1038/onc.2015.528. |
Links |
J:230651 – MGI References 26820992 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| C57BL/6J | Clitoral gland squamous cell carcinoma | Clitoral gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Clitoral gland squamous cell carcinoma | Clitoral gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Clitoral gland squamous cell carcinoma | Clitoral gland |
10.53 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Clitoral gland squamous cell carcinoma | Clitoral gland |
7.41 |
||
| C57BL/6J | Ear - Zymbal gland squamous cell carcinoma | Ear - Zymbal gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Ear - Zymbal gland squamous cell carcinoma | Ear - Zymbal gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Ear - Zymbal gland squamous cell carcinoma | Ear - Zymbal gland |
23.68 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Ear - Zymbal gland squamous cell carcinoma | Ear - Zymbal gland |
7.41 |
||
| C57BL/6J | Eye - Meibomian gland squamous cell carcinoma | Eye - Meibomian gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Eye - Meibomian gland squamous cell carcinoma | Eye - Meibomian gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Eye - Meibomian gland squamous cell carcinoma | Eye - Meibomian gland |
5.26 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Eye - Meibomian gland squamous cell carcinoma | Eye - Meibomian gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks Trp53tm1Brn | Mammary gland adenomyoepithelioma | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland adenomyoepithelioma | Mammary gland |
0 - observed |
||
| C57BL/6J | Mammary gland adenomyoepithelioma | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland adenomyoepithelioma | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland adenomyoepithelioma | Mammary gland |
observed |
||
| C57BL/6J | Mammary gland carcinoma | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinoma | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland carcinoma | Mammary gland |
63.16 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinoma | Mammary gland |
70.37 |
||
| C57BL/6J | Mammary gland carcinoma - acinar | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinoma - acinar | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland carcinoma - acinar | Mammary gland |
2.63 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinoma - acinar | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks Trp53tm1Brn | Mammary gland carcinoma - adenosquamous | Mammary gland |
observed |
||
| C57BL/6J | Mammary gland carcinoma - adenosquamous | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinoma - adenosquamous | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland carcinoma - adenosquamous | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinoma - adenosquamous | Mammary gland |
3.7 |
||
| C57BL/6J | Mammary gland carcinoma - cribriform | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinoma - cribriform | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland carcinoma - cribriform | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinoma - cribriform | Mammary gland |
0 |
||
| C57BL/6J | Mammary gland carcinoma - glandular | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinoma - glandular | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland carcinoma - glandular | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinoma - glandular | Mammary gland |
3.7 |
||
| C57BL/6J | Mammary gland carcinoma - papillary | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinoma - papillary | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland carcinoma - papillary | Mammary gland |
2.63 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinoma - papillary | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks Trp53tm1Brn | Mammary gland carcinoma - solid | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinoma - solid | Mammary gland |
observed |
||
| C57BL/6J | Mammary gland carcinoma - solid | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinoma - solid | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland carcinoma - solid | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinoma - solid - moderately differentiated | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinoma - solid - poorly differentiated | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks Trp53tm1Brn | Mammary gland carcinosarcoma | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland carcinosarcoma | Mammary gland |
observed - 3.7 |
||
| C57BL/6J | Mammary gland carcinosarcoma | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland carcinosarcoma | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland carcinosarcoma | Mammary gland |
observed |
||
| C57BL/6J | Mammary gland cyst - squamous | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland cyst - squamous | Mammary gland |
0 - observed |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland cyst - squamous | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland cyst - squamous | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland lesion | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland lesion | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland lesion - adenosquamous | Mammary gland |
observed |
||
| C57BL/6J | Mammary gland mammary intraepithelial neoplasia (MIN) | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland mammary intraepithelial neoplasia (MIN) | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland mammary intraepithelial neoplasia (MIN) | Mammary gland |
0 - 78.95 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland mammary intraepithelial neoplasia (MIN) | Mammary gland |
0 - 29.63 |
||
| C57BL/6J | Mammary gland mammary intraepithelial neoplasia (MIN) - adenosquamous | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland mammary intraepithelial neoplasia (MIN) - adenosquamous | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland mammary intraepithelial neoplasia (MIN) - adenosquamous | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland mammary intraepithelial neoplasia (MIN) - adenosquamous | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland mammary intraepithelial neoplasia (MIN) - high grade | Mammary gland |
28.57 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland mammary intraepithelial neoplasia (MIN) - low grade | Mammary gland |
observed |
||
| C57BL/6J | Mammary gland mammary intraepithelial neoplasia (MIN) - solid | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland mammary intraepithelial neoplasia (MIN) - solid | Mammary gland |
0 - observed |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland mammary intraepithelial neoplasia (MIN) - solid | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland mammary intraepithelial neoplasia (MIN) - solid | Mammary gland |
29.63 |
||
| C57BL/6J | Mammary gland metaplasia - cartilaginous | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland metaplasia - cartilaginous | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland metaplasia - cartilaginous | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland metaplasia - cartilaginous | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks Trp53tm1Brn | Mammary gland neoplasia - epithelial | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland neoplasia - epithelial | Mammary gland |
observed |
||
| C57BL/6J-Rad51ctm1Sks Trp53tm1Brn | Mammary gland tumor | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks Trp53tm1Brn | Mammary gland tumor | Mammary gland |
100 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland tumor | Mammary gland |
observed - 92.59 |
||
| C57BL/6J-Trp53tm1Brn | Mammary gland tumor | Mammary gland |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mammary gland tumor | Mammary gland |
0 - 60.53 |
||
| C57BL/6J | Mammary gland tumor | Mammary gland |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mammary gland tumor | Mammary gland |
2.63 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks/+ Trp53tm1Brn | Mammary gland tumor | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks Trp53tm1Brn | Mammary gland tumor - sarcomatous | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mammary gland tumor - sarcomatous | Mammary gland |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks Trp53tm1Brn | Mammary gland tumor - squamous | Mammary gland |
observed |
||
| C57BL/6J | Mesodermal cell/mesoblast sarcoma | Muscle |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Mesodermal cell/mesoblast sarcoma | Muscle |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Mesodermal cell/mesoblast sarcoma | Muscle |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Mesodermal cell/mesoblast sarcoma | Muscle |
7.41 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Muscle myosarcoma | Muscle |
7.41 |
||
| C57BL/6J | Muzzle carcinoma | Muzzle |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Muzzle carcinoma | Muzzle |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Muzzle carcinoma | Muzzle |
18.42 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Muzzle carcinoma | Muzzle |
3.7 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Salivary gland squamous cell carcinoma | Salivary gland |
3.7 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Skin - Epidermis cyst | Skin - Epidermis |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Skin - Epidermis cyst | Skin - Epidermis |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Skin - Epidermis papilloma | Skin - Epidermis |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Skin - Epidermis papilloma | Skin - Epidermis |
observed |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Skin gland - Sebaceous gland squamous cell carcinoma | Skin gland - Sebaceous gland |
18.92 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Skin gland - Sebaceous gland squamous cell carcinoma | Skin gland - Sebaceous gland |
7.41 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Skin gland - Sebaceous gland tumor | Skin gland - Sebaceous gland |
57.89 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Skin gland - Sebaceous gland tumor | Skin gland - Sebaceous gland |
14.81 |
||
| C57BL/6J | Skin lesion | Skin |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Skin lesion | Skin |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Skin lesion | Skin |
23.68 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Skin lesion | Skin |
7.41 |
||
| C57BL/6J | Skin squamous cell carcinoma | Skin |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Skin squamous cell carcinoma | Skin |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | Skin squamous cell carcinoma | Skin |
52.63 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Skin squamous cell carcinoma | Skin |
14.81 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | Skin tumor | Skin |
50 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | Skin tumor | Skin |
18.52 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Trp53tm1Brn | (Unspecified organ) tumor | (Unspecified organ) |
7.41 - 81.48 |
||
| C57BL/6J | (Unspecified organ) tumor | (Unspecified organ) |
0 |
||
| C57BL/6J-Krt14tm1.1(cre)Wbm/+ Rad51ctm1Sks | (Unspecified organ) tumor | (Unspecified organ) |
0 |
||
| B6.Cg-Ptentm4.1Ppp/+ | (Unspecified organ) tumor | (Unspecified organ) |
100 |
||
| NFS.V | (Unspecified organ) tumor | (Unspecified organ) |
100 |