Tumor Suppressor Biology
Tumor suppressor genes normally function to restrict cell proliferation, promote apoptosis, maintain genomic stability, or repair DNA damage. Loss of tumor suppressor function through mutation or deletion enables uncontrolled cell growth and is a hallmark of cancer development.
Categories of Tumor Suppressors
Gatekeeper Genes
Gatekeeper genes directly regulate cell proliferation or death. Loss of gatekeepers such as Rb or p53 immediately promotes cellular transformation.
Caretaker Genes
Caretaker genes maintain genomic integrity through DNA repair or chromosome segregation. Loss of caretakers such as BRCA1 or MLH1 leads to accumulation of mutations and genomic instability.
Landscaper Genes
Landscaper genes affect the tissue microenvironment and influence tumor development indirectly through effects on stroma or immune cells.
Common Tumor Suppressor Targets
p53 (Trp53)
p53 is mutated or deleted in the majority of human cancers. Constitutive p53 knockout mice develop tumors spontaneously, while conditional p53 knockouts enable tissue specific tumor studies without early mortality.
p53 conditional alleles crossed with tissue specific Cre lines enable study of p53 loss in specific organs such as lung, breast, colon, or hematopoietic system.
Rb (Rb1)
The retinoblastoma protein controls G1/S cell cycle transition. Rb knockout mice develop pituitary and thyroid tumors, while conditional Rb deletion enables study of tissue specific effects.
PTEN
PTEN is a phosphatase that negatively regulates the PI3K/AKT pathway. PTEN loss occurs commonly in prostate, breast, and brain cancers. Conditional PTEN knockouts develop tissue specific tumors with high penetrance.
APC
APC mutations drive colorectal cancer through constitutive Wnt signaling activation. APC conditional knockouts enable study of intestinal adenoma development and progression to carcinoma.
BRCA1 and BRCA2
BRCA genes maintain genomic stability through homologous recombination DNA repair. Conditional BRCA knockouts in mammary or ovarian epithelium enable study of hereditary breast and ovarian cancer.
Knockout Strategy Considerations
Constitutive vs Conditional Knockout
Constitutive tumor suppressor knockouts often cause embryonic lethality or early death from tumors, limiting their utility for studying adult cancer. Conditional knockouts enable tumor suppressor deletion in specific tissues at defined times.
Learn moreTissue Specific Deletion
Crossing conditional (floxed) tumor suppressor alleles with tissue specific Cre lines enables gene deletion in the tissue of interest. This approach generates tumors in clinically relevant organs without affecting other tissues.
Common Cre drivers for cancer models include MMTV Cre (mammary), Villin Cre (intestine), Albumin Cre (liver), K14 Cre (skin), and GFAP Cre (brain).
Inducible Deletion
Tamoxifen inducible Cre lines enable temporal control over tumor suppressor deletion. This approach models sporadic tumor development and enables study of tumor suppressor loss in adult tissues.
Learn moreMulti Gene Cancer Models
Compound Knockouts
Cancer typically requires loss of multiple tumor suppressors. Compound conditional knockouts enable simultaneous deletion of multiple genes to study cooperating mutations.
Common combinations include p53/PTEN double knockouts, p53/Rb double knockouts, and APC/p53 combinations.
Tumor Suppressor Plus Oncogene
Combining tumor suppressor knockout with oncogene activation generates aggressive tumor models. Conditional Kras activation combined with p53 deletion is widely used for lung and pancreatic cancer models.
Applications
Tumor Biology Studies
Tumor suppressor knockouts enable study of cancer initiation, progression, and metastasis in physiologically relevant contexts.
Drug Development
Genetically defined tumor models enable preclinical testing of targeted therapies and evaluation of synthetic lethal approaches.
Biomarker Discovery
Models with defined genetic lesions support identification of biomarkers associated with tumor suppressor loss.
Immunotherapy Studies
Tumor suppressor knockout models on immunocompetent backgrounds enable study of tumor immune interactions and testing of immunotherapies.
What Researchers Say
“I'd like to thank the ingenious team for making this mouse for us. We are so excited! Everyone at ingenious has been wonderful to work with throughout the entire process. We will definitely be in contact the next time we need a mouse!”
— Julia Maxson, PhD
Knight Cancer Institute, Oregon Health & Science University
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