RGD Reference Report - Deletion of Cdkn1b in ACI rats leads to increased proliferation and pregnancy-associated changes in the mammary gland due to perturbed systemic endocrine environment. - Rat Genome Database

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Deletion of Cdkn1b in ACI rats leads to increased proliferation and pregnancy-associated changes in the mammary gland due to perturbed systemic endocrine environment.

Authors: Ding, Lina  Shunkwiler, Lauren B  Harper, Nicholas W  Zhao, Yang  Hinohara, Kunihiko  Huh, Sung Jin  Ekram, Muhammad B  Guz, Jan  Kern, Michael J  Awgulewitsch, Alexander  Shull, James D  Smits, Bart M G  Polyak, Kornelia 
Citation: Ding L, etal., PLoS Genet. 2019 Mar 20;15(3):e1008002. doi: 10.1371/journal.pgen.1008002. eCollection 2019 Mar.
RGD ID: 126908018
Pubmed: PMID:30893315   (View Abstract at PubMed)
PMCID: PMC6443185   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pgen.1008002   (Journal Full-text)

Mammary epithelial progenitors are the normal cell-of-origin of breast cancer. We previously defined a population of p27+ quiescent hormone-responsive progenitor cells in the normal human breast whose frequency associates with breast cancer risk. Here, we describe that deletion of the Cdkn1b gene encoding the p27 cyclin-dependent kinase inhibitor in the estrogen-induced mammary tumor-susceptible ACI rat strain leads to a decrease in the relative frequencies of Cd49b+ mammary luminal epithelial progenitors and pregnancy-related differentiation. We show by comprehensive gene expression profiling of purified progenitor and differentiated mammary epithelial cell populations that p27 deletion has the most pronounced effects on luminal progenitors. Cdkn1b-/- females have decreased fertility, but rats that are able to get pregnant had normal litter size and were able to nurse their pups implying that loss of p27 in ACI rats does not completely abrogate ovarian function and lactation. Reciprocal mammary gland transplantation experiments indicate that the p27-loss-induced changes in mammary epithelial cells are not only caused by alterations in their intrinsic properties, but are likely due to altered hormonal signaling triggered by the perturbed systemic endocrine environment observed in Cdkn1b-/- females. We also observed a decrease in the frequency of mammary epithelial cells positive for progesterone receptor (Pr) and FoxA1, known direct transcriptional targets of the estrogen receptor (Erα), and an increase in phospho-Stat5 positive cells commonly induced by prolactin (Prl). Characterization of genome-wide Pr chromatin binding revealed distinct binding patterns in mammary epithelial cells of Cdkn1b+/+ and Cdkn1b-/- females and enrichment in genes with known roles in Notch, ErbB, leptin, and Erα signaling and regulation of G1-S transition. Our data support a role for p27 in regulating the pool size of hormone-responsive luminal progenitors that could impact breast cancer risk.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ACI.Cg.-Cdkn1bem1MuscRatabnormal mammary gland luminal epithelium morphology  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatabnormal mammary gland luminal epithelium morphology  IMP  RGD 
Cdkn1bRatabnormal mammary gland luminal epithelium morphology  IMP  RGD 
Cdkn1bem1MuscRatabnormal mammary gland luminal epithelium morphology  IMP  RGD 
Cdkn1bem4MuscRatabnormal mammary gland luminal epithelium morphology  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatcataract  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatcataract  IMP  RGD 
Cdkn1bRatcataract  IMP in KO ratRGD 
Cdkn1bem1MuscRatcataract  IMP  RGD 
Cdkn1bem4MuscRatcataract  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased body weight  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased body weight  IMP  RGD 
Cdkn1bRatincreased body weight  IMP in KO ratRGD 
Cdkn1bem1MuscRatincreased body weight  IMP  RGD 
Cdkn1bem4MuscRatincreased body weight  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased brain weight  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased brain weight  IMP  RGD 
Cdkn1bRatincreased brain weight  IMP in KO ratRGD 
Cdkn1bem1MuscRatincreased brain weight  IMP  RGD 
Cdkn1bem4MuscRatincreased brain weight  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased circulating estradiol level  IMP at 9 weeksRGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased circulating estradiol level  IMP at 9 weeksRGD 
Cdkn1bRatincreased circulating estradiol level  IMP in KO ratRGD 
Cdkn1bem1MuscRatincreased circulating estradiol level  IMP at 9 weeksRGD 
Cdkn1bem4MuscRatincreased circulating estradiol level  IMP at 9 weeksRGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased circulating prolactin level  IMP at 4-6 weeksRGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased circulating prolactin level  IMP at 4-6 weeksRGD 
Cdkn1bRatincreased circulating prolactin level  IMP at 4-6 weeksRGD 
Cdkn1bem1MuscRatincreased circulating prolactin level  IMP at 4-6 weeksRGD 
Cdkn1bem4MuscRatincreased circulating prolactin level  IMP at 4-6 weeksRGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased liver weight  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased liver weight  IMP  RGD 
Cdkn1bRatincreased liver weight  IMP in KO ratRGD 
Cdkn1bem1MuscRatincreased liver weight  IMP  RGD 
Cdkn1bem4MuscRatincreased liver weight  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased lung weight  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased lung weight  IMP  RGD 
Cdkn1bRatincreased lung weight  IMP in KO ratRGD 
Cdkn1bem1MuscRatincreased lung weight  IMP  RGD 
Cdkn1bem4MuscRatincreased lung weight  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased mammary fat pad weight  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased mammary fat pad weight  IMP  RGD 
Cdkn1bRatincreased mammary fat pad weight  IMP  RGD 
Cdkn1bem1MuscRatincreased mammary fat pad weight  IMP  RGD 
Cdkn1bem4MuscRatincreased mammary fat pad weight  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased mammary gland epithelial cell proliferation  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased mammary gland epithelial cell proliferation  IMP  RGD 
Cdkn1bRatincreased mammary gland epithelial cell proliferation  IMP  RGD 
Cdkn1bem1MuscRatincreased mammary gland epithelial cell proliferation  IMP  RGD 
Cdkn1bem4MuscRatincreased mammary gland epithelial cell proliferation  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased pituitary gland weight  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased pituitary gland weight  IMP  RGD 
Cdkn1bRatincreased pituitary gland weight  IMP in KO ratRGD 
Cdkn1bem1MuscRatincreased pituitary gland weight  IMP  RGD 
Cdkn1bem4MuscRatincreased pituitary gland weight  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased spleen weight  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased spleen weight  IMP  RGD 
Cdkn1bRatincreased spleen weight  IMP in KO ratRGD 
Cdkn1bem1MuscRatincreased spleen weight  IMP  RGD 
Cdkn1bem4MuscRatincreased spleen weight  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatincreased thymus weight  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatincreased thymus weight  IMP  RGD 
Cdkn1bRatincreased thymus weight  IMP in KO ratRGD 
Cdkn1bem1MuscRatincreased thymus weight  IMP  RGD 
Cdkn1bem4MuscRatincreased thymus weight  IMP  RGD 
ACI.Cg.-Cdkn1bem1MuscRatreduced fertility  IMP  RGD 
ACI.Cg.-Cdkn1bem4MuscRatreduced fertility  IMP  RGD 
Cdkn1bRatreduced fertility  IMP in KO ratRGD 
Cdkn1bem1MuscRatreduced fertility  IMP  RGD 
Cdkn1bem4MuscRatreduced fertility  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Cdkn1b  (cyclin-dependent kinase inhibitor 1B)
Cdkn1bem1Musc  (cyclin-dependent kinase inhibitor 1B; CRISPR/Cas9 induced mutant 1, Musc)
Cdkn1bem4Musc  (cyclin-dependent kinase inhibitor 1B; CRISPR/Cas9 induced mutant 4, Musc)

Genes (Mus musculus)
Cdkn1b  (cyclin dependent kinase inhibitor 1B)

Genes (Homo sapiens)
CDKN1B  (cyclin dependent kinase inhibitor 1B)


Additional Information