Phenotypes associated with this allele

• Allele Symbol: Frmd3^em1Zhaj
• Allele Name: endonuclease-mediated mutation 1, Jun Zhan
• Allele ID: MGI:7664563
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Frmd3^em1Zhaj/Frmd3^em1Zhaj	C57BL/6J-Frmd3^em1Zhaj	MGI:7834417
cx2	Frmd3^em1Zhaj/Frmd3^em1Zhaj Tg(MMTV-PyVT)634Mul/0	B6.Cg-Frmd3^em1Zhaj Tg(MMTV-PyVT)634Mul	MGI:7834434

Genotype
MGI:7834417

hm1

• Allelic Composition: Frmd3^em1Zhaj/Frmd3^em1Zhaj
• Genetic Background: C57BL/6J-Frmd3^em1Zhaj

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

neoplasm

increased mammary gland tumor incidence ( J:350496 )

• mice begin to develop mammary tumors at 8 months of age, with a total tumor incidence of 65%

• all premalignant lesions contain mammary epithelia cells (MECs) with a luminal-to-basal change

increased mammary gland ductal carcinoma incidence ( J:350496 )

• tumors have abundant blood vessels and adhere to surrounding tissues and have a typical invasive ductal carcinoma morphology

• approximately 70% of tumors show glandular differentiation with mild inflammation (type 1) and about 25% of tumors are grade 3 carcinomas (type 2) with syncytial growth, pushing border, large pleomorphic nuclei, conspicuous mitoses, and regions of necrosis, and a few poorly differentiated or metaplastic carcinomas

• all tumors exhibit heterogenous regions with squamous, papillary, giant cell, and glandular histological characteristics and are triple negative (ER-, PR-, and HER2-) and highly proliferative

• the type 1 tumors have lost luminal features and show triple-negative breast cancer phenotype

• type 2 tumors are most similar to claudin-low subtype

endocrine/exocrine glands

abnormal mammary gland morphology ( J:350496 )

• expansion of mammary stem cells

• mammary epithelial cells generate an increased number and large size of mammospheres, indicating enhanced self-renewal ability of mammary stem cells

• estrogen receptor alpha and progesterone receptor levels are decreased in mammary glands at 8 weeks of age

abnormal mammary gland development ( J:350496 )

• in early puberty (weeks 3 to 5), the mammary gland distribution area is increased but is similar to wild-type after this time in late puberty at week 8

• early puberty mammary glands show an increase in mammary stem cell basal/myoepithelial population and a decrease in luminal population and terminal end buds of mammary glands show a decreased number of CK8+ luminal cells and increased number of CK5+ basal cells at 5 weeks of age and increased CK5 and no CK8 expression in mammary gland branches at 8 weeks of age indicating expansion of basal cells and inhibition of luminal cell differentiation

• terminal end bud of mammary glands at 5 weeks of age show increased cell proliferation especially in the cap, indicating a transient fast-growing period in early puberty

abnormal branching of the mammary ductal tree ( J:350496 )

• mice show impaired ductal complexity and a decreased number of primary and secondary mammary side branches such that by week 12, the mammary gland has no tertiary branches

impaired mammary gland growth during pregnancy ( J:350496 )

• acinar formation during pregnancy is decreased in the mammary gland

abnormal mammary gland luminal epithelium morphology ( J:350496 )

• mammary gland shows inhibition of luminal cell differentiation with impaired luminal lineage formation resulting in loss of luminal identity and gain of basal properties

• all premalignant lesions contain mammary epithelia cells with a luminal-to-basal change

abnormal mammary gland myoepithelium morphology ( J:350496 )

• mammary gland shows expansion of basal cells

increased mammary gland tumor incidence ( J:350496 )

• mice begin to develop mammary tumors at 8 months of age, with a total tumor incidence of 65%

• all premalignant lesions contain mammary epithelia cells (MECs) with a luminal-to-basal change

increased mammary gland ductal carcinoma incidence ( J:350496 )

• tumors have abundant blood vessels and adhere to surrounding tissues and have a typical invasive ductal carcinoma morphology

• approximately 70% of tumors show glandular differentiation with mild inflammation (type 1) and about 25% of tumors are grade 3 carcinomas (type 2) with syncytial growth, pushing border, large pleomorphic nuclei, conspicuous mitoses, and regions of necrosis, and a few poorly differentiated or metaplastic carcinomas

• all tumors exhibit heterogenous regions with squamous, papillary, giant cell, and glandular histological characteristics and are triple negative (ER-, PR-, and HER2-) and highly proliferative

• the type 1 tumors have lost luminal features and show triple-negative breast cancer phenotype

• type 2 tumors are most similar to claudin-low subtype

integument

abnormal mammary gland morphology ( J:350496 )

• expansion of mammary stem cells

• mammary epithelial cells generate an increased number and large size of mammospheres, indicating enhanced self-renewal ability of mammary stem cells

• estrogen receptor alpha and progesterone receptor levels are decreased in mammary glands at 8 weeks of age

abnormal mammary gland development ( J:350496 )

• in early puberty (weeks 3 to 5), the mammary gland distribution area is increased but is similar to wild-type after this time in late puberty at week 8

• early puberty mammary glands show an increase in mammary stem cell basal/myoepithelial population and a decrease in luminal population and terminal end buds of mammary glands show a decreased number of CK8+ luminal cells and increased number of CK5+ basal cells at 5 weeks of age and increased CK5 and no CK8 expression in mammary gland branches at 8 weeks of age indicating expansion of basal cells and inhibition of luminal cell differentiation

• terminal end bud of mammary glands at 5 weeks of age show increased cell proliferation especially in the cap, indicating a transient fast-growing period in early puberty

abnormal branching of the mammary ductal tree ( J:350496 )

• mice show impaired ductal complexity and a decreased number of primary and secondary mammary side branches such that by week 12, the mammary gland has no tertiary branches

impaired mammary gland growth during pregnancy ( J:350496 )

• acinar formation during pregnancy is decreased in the mammary gland

abnormal mammary gland luminal epithelium morphology ( J:350496 )

• mammary gland shows inhibition of luminal cell differentiation with impaired luminal lineage formation resulting in loss of luminal identity and gain of basal properties

• all premalignant lesions contain mammary epithelia cells with a luminal-to-basal change

abnormal mammary gland myoepithelium morphology ( J:350496 )

• mammary gland shows expansion of basal cells

increased mammary gland tumor incidence ( J:350496 )

• mice begin to develop mammary tumors at 8 months of age, with a total tumor incidence of 65%

• all premalignant lesions contain mammary epithelia cells (MECs) with a luminal-to-basal change

increased mammary gland ductal carcinoma incidence ( J:350496 )

• tumors have abundant blood vessels and adhere to surrounding tissues and have a typical invasive ductal carcinoma morphology

• approximately 70% of tumors show glandular differentiation with mild inflammation (type 1) and about 25% of tumors are grade 3 carcinomas (type 2) with syncytial growth, pushing border, large pleomorphic nuclei, conspicuous mitoses, and regions of necrosis, and a few poorly differentiated or metaplastic carcinomas

• all tumors exhibit heterogenous regions with squamous, papillary, giant cell, and glandular histological characteristics and are triple negative (ER-, PR-, and HER2-) and highly proliferative

• the type 1 tumors have lost luminal features and show triple-negative breast cancer phenotype

• type 2 tumors are most similar to claudin-low subtype

reproductive system

impaired mammary gland growth during pregnancy ( J:350496 )

• acinar formation during pregnancy is decreased in the mammary gland

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
triple-receptor negative breast cancer		DOID:0060081		J:350496

Genotype
MGI:7834434

cx2

• Allelic Composition: Frmd3^em1Zhaj/Frmd3^em1Zhaj; Tg(MMTV-PyVT)634Mul/0
• Genetic Background: B6.Cg-Frmd3^em1Zhaj Tg(MMTV-PyVT)634Mul

neoplasm

increased mammary gland tumor incidence ( J:350496 )

• mice show larger volume and increased number of tumors at 120 days of age than in single Tg(MMTV-PyVT)634Mul/0 mice

• tumors show syncytial growth, a pushing border, and areas of necrosis with increased proliferation at the invasive edge

• following orthotopic transplantation into wild-type recipient mice, mutant cells show a higher tumor incidence, and have a larger volume and higher proliferation, indicating increased stemness of cancer

increased mammary adenocarcinoma incidence ( J:350496 )

• in late stage carcinoma, tumors are estrogen receptor-negative and progesterone receptor negative (ER-PR-)

• tumors show up-regulation of CK5 and down-regulation of CK8, indicating expansion of basal cells and inhibition of luminal cell differentiation

increased tumor growth/size ( J:350496 )

• mammary glands exhibit fewer but larger tumors at week 9 (preneoplastic stage) than in single Tg(MMTV-PyVT)634Mul/0 mice

• primary tumor cells form more and larger mammospheres at day 5 of culture than tumor cells from single Tg(MMTV-PyVT)634Mul/0 mice

decreased tumor latency ( J:350496 )

• mice show accelerated mammary gland tumor progression compared to single Tg(MMTV-PyVT)634Mul/0 mice

• however, overall tumor-free survival duration is similar to single Tg(MMTV-PyVT)634Mul/0 mice

endocrine/exocrine glands

increased mammary gland epithelial cell proliferation ( J:350496 )

• increase in the number of proliferating cells in mammary glands at weeks 6 and 8 compared to single Tg(MMTV-PyVT)634Mul/0 mice

increased mammary gland tumor incidence ( J:350496 )

• mice show larger volume and increased number of tumors at 120 days of age than in single Tg(MMTV-PyVT)634Mul/0 mice

• tumors show syncytial growth, a pushing border, and areas of necrosis with increased proliferation at the invasive edge

• following orthotopic transplantation into wild-type recipient mice, mutant cells show a higher tumor incidence, and have a larger volume and higher proliferation, indicating increased stemness of cancer

increased mammary adenocarcinoma incidence ( J:350496 )

• in late stage carcinoma, tumors are estrogen receptor-negative and progesterone receptor negative (ER-PR-)

• tumors show up-regulation of CK5 and down-regulation of CK8, indicating expansion of basal cells and inhibition of luminal cell differentiation

increased mammary gland apoptosis ( J:350496 )

• enhanced apoptosis is seen in mammary glands at weeks 6 and 8 compared to single Tg(MMTV-PyVT)634Mul/0 mice

integument

increased mammary gland epithelial cell proliferation ( J:350496 )

• increase in the number of proliferating cells in mammary glands at weeks 6 and 8 compared to single Tg(MMTV-PyVT)634Mul/0 mice

increased mammary gland tumor incidence ( J:350496 )

• mice show larger volume and increased number of tumors at 120 days of age than in single Tg(MMTV-PyVT)634Mul/0 mice

• tumors show syncytial growth, a pushing border, and areas of necrosis with increased proliferation at the invasive edge

• following orthotopic transplantation into wild-type recipient mice, mutant cells show a higher tumor incidence, and have a larger volume and higher proliferation, indicating increased stemness of cancer

increased mammary adenocarcinoma incidence ( J:350496 )

• in late stage carcinoma, tumors are estrogen receptor-negative and progesterone receptor negative (ER-PR-)

• tumors show up-regulation of CK5 and down-regulation of CK8, indicating expansion of basal cells and inhibition of luminal cell differentiation

increased mammary gland apoptosis ( J:350496 )

• enhanced apoptosis is seen in mammary glands at weeks 6 and 8 compared to single Tg(MMTV-PyVT)634Mul/0 mice

cellular

increased mammary gland epithelial cell proliferation ( J:350496 )

• increase in the number of proliferating cells in mammary glands at weeks 6 and 8 compared to single Tg(MMTV-PyVT)634Mul/0 mice