• homozygous embryos die at midgestation similar to Kras^tm1Tyi

• tamoxifen-treated mice exhibit reduced tumor burden and tumor grade compared with similarly treated Kras^tm1Bbd/Kras⁺ Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• tamoxifen-treated mice exhibit an increase in lifespan compared with similarly treated Kras^tm1Bbd/Kras⁺ Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} littermates

• tamoxifen-treated mice exhibit reduced tumor burden and tumor grade compared with similarly treated Kras^tm1Bbd/Kras⁺ Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• 50% survival for tamoxifen-treated mice is 25 weeks compared with 42 weeks for similarly treated Kras^tm1Bbd/Kras⁺ Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} littermates

• lung tumors in tamoxifen-treated mice are more aggressive than in similarly treated Kras^tm1Bbd/Kras⁺ Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• however, treatment with the Cdk4 inhibitor PD0332991 reduces tumor formation

• in mice treated with tamoxifen

• proliferation of lung cells in tamoxifen-treated mice exhibit 8- to 10-fold greater proliferation than in Cdk4^tm2.1Bbd/Cdk4^tm2.1Bbd Kras^tm1Bbd/Kras^tm2Bbd Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• lung cells in tamoxifen-treated mice exhibit 8- to 10-fold reduction in proliferation and early senescence compared to in similarly treated Kras^tm1Bbd/Kras^tm2Bbd Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• tamoxifen-treated mice exhibit adenocarcinomas that are not as severe as in Kras^tm1Bbd/Kras^tm2Bbd Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• proliferation of lung cells in tamoxifen-treated mice exhibit 8- to 10-fold less proliferation than in similarly treated Kras^tm1Bbd/Kras^tm2Bbd Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• tamoxifen-treated mice exhibit increased cell replicative senescence in the lungs compared to in similarly treated Kras^tm1Bbd/Kras^tm2Bbd Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• tamoxifen-treated mice infected with a flp-expressing adenovirus exhibit decreased proliferation and early senescence of tumor cells compared with tamoxifen and infected with GFP-expressing adenovirus

• tamoxifen-treated mice infected with a flp-expressing adenovirus exhibit reduced lesions compared to in mice treated with tamoxifen and infected with GFP-expressing adenovirus

• in tamoxifen-treated mice as in similarly treated Kras^tm1Bbd/Kras^tm2Bbd Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• tamoxifen-treated mice infected with a flp-expressing adenovirus exhibit early senescence of tumor cells compared with tamoxifen and infected with GFP-expressing adenovirus

• tamoxifen-treated mice infected with a flp-expressing adenovirus exhibit decreased proliferation of tumor cells compared with tamoxifen and infected with GFP-expressing adenovirus

• the mean lifespan of mice treated tamoxifen is 34-42 weeks

• in mice treated with tamoxifen at weaning

• in mice treated with tamoxifen at weaning

• 50% of tamoxifen-treated mice survive at 40 weeks

• in mice treated with tamoxifen at weaning

• in mice treated with tamoxifen at weaning

• mice treated tamoxifen at weaning exhibit an increase in lifespan of 8 weeks (42 weeks) compared with similarly treated Kras^tm1Bbd/Kras⁺ Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} littermates (34 weeks)

• tamoxifen-treated mice exhibit reduced tumor burden compared with similarly treated Kras^tm1Bbd/Kras⁺ Polr2a^{tm1(cre/ERT2)Bbd}/Polr2a^{tm1(cre/ERT2)Bbd} mice

• double mutants develop breathing difficulties after 7 - 8 months of age

• frequent embryonic lethality; however, a significant number of double mutants survive

• a large spectrum of multifocal lesions are seen in the lung including; small patches of bronchiolo-alveolar hyperplasias to large bronchiolo-alveolar adenomas that compress adjacent lung structures and appear to derive from type II pneumocytes

• anal papillomas seen in 3 out of 20 double mutants

• large bronchiolo-alveolar adenocarcinomas that compress adjacent lung structures and appear to derive from type II pneumocytes

• histiocytic sarcoma and other sarcomas seen in 2 out of 20 and 3 out of 20 double mutants, respectively

• MEFs expressing the oncogenic protein do not undergo proliferative senescence and proliferate continuously as immortal cells

• double mutants develop breathing difficulties after 7 - 8 months of age

• latency to develop lung adenomas is significantly shorter compared to double mutants wild-type for Cdk4; however development of tumors characteristic of Cdk4^tm1.1Bbd mutant mice is not accelerated

• anal papillomas are seen

• histiocytic sarcoma and other sarcomas are seen

• focal metaplasia in the pancreatic ducts consisting of tall columnar cells with abundant apical mucin resembling gastric surface epithelial cells

• focal metaplasia in the pancreatic ducts consisting of tall columnar cells with abundant apical mucin resembling gastric surface epithelial cells

• after treatment with 4-hydroxy-tamoxifen for 24 weeks multiple lung adenomas develop by 7 months of age; however no difference in the latency, number, or size of tumors was seen compared to double mutants wild-type for Fntb

• after treatment with 4-hydroxy-tamoxifen for 24 weeks multiple lung adenocarcinomas develop by 7 months of age; however no difference in the latency, number, or size of tumors was seen compared to double mutants wild-type for Fntb

• mice die before week 32 due to increased lung cancer progression

• lung differentiation is abnormal with increased SP-C-positive cells

• 20 weeks after treatment, lungs are increased in size

• mice also have tumors in the thymus and organs such as kidney and liver by 24 weeks after treatment whereas controls only have tumors in lungs and thymus

• 2 weeks after 5-hydroxytamoxifen treatment, small tumors are found in the lungs

• 20 weeks after treatment, lungs are oversized with 2-3 times as many tumors, many often >2mm in diameter, while lungs of Kras, Mapk14 heterozygotes have normal lungs with fewer, smaller tumors; tumors in Mapk14 homozygotes are more poorly differentiated and have higher mitotic indices

• at 26 weeks, total tumor number is slightly higher than in controls with much higher numbers of tumors larger than 2 mm in diameter and a higher ratio of lung mass to total mass

• tumors are detected 2 weeks after 5-hydroxytamoxifen treatment and after 4 weeks, clear signs of adenomas are present in most lungs compared to only a few small adenomas in lungs of treated Kras, Mapk14^tm2Nbr/+ control mice

• adenocarcinomas are detected at 15 weeks but not in controls

• mice live up to 40 weeks

• by 24 weeks, mice develop tumors in lungs and thymus

• at 4 weeks after 5-hydroxytamoxifen treatment, a few small adenomas are observed in some animals

• at 200 days, 100% of mice exhibit atypical hypoplasia unlike wild-type mice (J:143043)

• at 500 days, 93% of mice exhibit atypical hypoplasia unlike wild-type mice (J:143043)

• in 7% of mice at 500 days (J:143043)

• at 200 days, 67% of mice develop prostate intraepithelial neoplasia that display foci of small solid and cribiform intraluminal proliferation of atypical cells and nuclear atypia unlike wild-type mice (J:143043)

• at 500 days, 60% of mice exhibit prostate intraepithelial neoplasia unlike in wild-type mice (J:143043)

• at 200 days, 100% of mice exhibit atypical hypoplasia unlike wild-type mice (J:143043)

• at 500 days, 93% of mice exhibit atypical hypoplasia unlike wild-type mice (J:143043)

• mice die prior to day 300

• mice exhibit keratinized squamous metaplasia in the bulbourethral gland unlike wild-type mice (J:143034)

• all mice develop diffuse, locally invasive carcinomas in the prostate that develop from solid or sheet-like proliferation with occasional rosette structures, nuclear atypia, apoptotic bodies, and mitosis unlike in wild-type mice (J:143034)

• mice exhibit keratinized squamous metaplasia in the urethral gland unlike wild-type mice

• mice exhibit keratinized squamous metaplasia in the bulbourethral gland unlike wild-type mice (J:143034)

• double mutants treated with 4-hydroxy-tamoxifen at 10 days of age develop breathing difficulties after 7 - 8 months of age

• after treatment with 4-hydroxy-tamoxifen at 10 days of age, a large spectrum of multifocal lesions are seen in the lung at 7-8 months of age including; small patches of bronchiolo-alveolar hyperplasias to large bronchiolo-alveolar adenomas that compress adjacent lung structures and appear to derive from type II pneumocytes

• after treatment with 4-hydroxy-tamoxifen at 10 days of age, at 7-8 months of age large bronchiolo-alveolar adenocarcinomas that compress adjacent lung structures and appear to derive from type II pneumocytes are seen

• MEFs expressing the oncogenic protein do not undergo proliferative senescence and proliferate continuously as immortal cells

• double mutants treated with 4-hydroxy-tamoxifen at 10 days of age develop breathing difficulties after 7 - 8 months of age

• hyperplastic Harderian gland seen in double mutants treated with 4-hydroxy-tamoxifen at 10 days of age