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

Autor: Kornelia Polyak, Alexander Awgulewitsch, Lina Ding, Yang Zhao, Muhammad B. Ekram, Lauren B. Shunkwiler, Jan Guz, James D. Shull, Michael J. Kern, Nicholas W. Harper, Bart M. G. Smits, Kunihiko Hinohara, Sung Jin Huh
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Cancer Research
Cellular differentiation
Maternal Health
Mammary gland
Integrin alpha1
Estrogen receptor
Gene Expression
Biochemistry
Epithelium
Animals
Genetically Modified
Rats
Sprague-Dawley
0302 clinical medicine
Pregnancy
Risk Factors
Animal Cells
Breast Tumors
Medicine and Health Sciences
Lipid Hormones
Genetics (clinical)
Progesterone
0303 health sciences
Chromatin binding
Stem Cells
Obstetrics and Gynecology
Cell Differentiation
Mammary Glands
3. Good health
medicine.anatomical_structure
Receptors
Estrogen
Oncology
Female
Anatomy
Cellular Types
Receptors
Progesterone
Cyclin-Dependent Kinase Inhibitor p27
Signal Transduction
Research Article
medicine.medical_specialty
lcsh:QH426-470
Breast Neoplasms
Biology
03 medical and health sciences
Mammary Glands
Animal
Exocrine Glands
Internal medicine
Progesterone receptor
Breast Cancer
medicine
Genetics
Animals
Humans
Genetic Predisposition to Disease
Mammary Glands
Human
Molecular Biology
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Cell Proliferation
Estrogen Receptor alpha
Reproductive System
Biology and Life Sciences
Cancers and Neoplasms
Epithelial Cells
Estrogens
Cell Biology
Prolactin
Hormones
Rats
Rats
Inbred ACI
lcsh:Genetics
Endocrinology
Biological Tissue
Women's Health
FOXA1
Endocrine Cells
Estrogen receptor alpha
Breast Tissue
030217 neurology & neurosurgery
Developmental Biology
Zdroj: PLoS Genetics, Vol 15, Iss 3, p e1008002 (2019)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: 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.
Author summary The frequency and proliferation of tissue-specific stem and progenitor cells is associated with the risk of malignancy. Thus, regulators of the pool size and proliferation of progenitor cells determine cancer risk. p27 is a key regulator of cellular proliferation and is required for the terminal differentiation of a number of cell types. Here we show that genetic deletion of Cdkn1b in ACI rats susceptible to estrogen-induced mammary tumors decreases the relative fraction of Cd49b+ luminal progenitors identifying p27 as a key regulator of the proliferation and pool size of these cells. Progesterone, acting via the progesterone receptor (Pr), is an important regulator of mammary epithelial cell proliferation and differentiation. Based on ChIP-seq we found that Pr targets different sets of genes in Cdkn1b+/+ and Cdkn1b-/- mammary epithelium and that this is associated with differences in proliferation and differentiation states. Thus, p27 regulates breast cancer risk and tumor development via regulating the pool size and hormonal-responsiveness of luminal progenitors.
Databáze: OpenAIRE
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