PTEN overexpression suppresses proliferation and differentiation and enhances apoptosis of the mouse mammary epithelium

Dupont, Joëlle; Renou, Jean-Pierre; Shani, Moshe; Hennighausen, Lothar; LeRoith, Derek

doi:10.1172/jci0213829

Cited by 83 publications

(38 citation statements)

References 53 publications

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“…The importance of activation of the insulin/PI3K/ Akt pathway in the functional differentiation of the mammary gland has been shown in genetic inhibition studies. Overexpression of active PTEN, a negative regulator of the pathway, in mammary epithelium causes a marked reduction in cell proliferation, an incomplete functional differentiation, and failure to lactate (46). Also, expression of constitutively activated Akt in the mammary glands of transgenic mice results in impaired lactation with excess lipid synthesis (47).…”

Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Regulates the Growth of Mammary Epithelial Cells through the Inhibitor of Deoxyribonucleic Acid Binding Id1 and Their Functional Differentiation through Id2

Jankiewicz

Groner

Desrivières

2006

Molecular Endocrinology

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Organ development requires the integration of multiple extracellular signals to assure a proper balance between proliferation and differentiation and to achieve and maintain specialized functions. Considerable progress has been made in the study of hormones and growth factors and in the understanding of the regulated intracellular pathways and transcriptional events that contribute to mammogenesis. Cell culture experiments have pointed out crucial pathways and components, which were subsequently validated in vivo experiments. We found that the mammalian target of rapamycin (mTOR) pathway is essential for both growth and differentiation of mammary epithelial cells and that the action of mTOR is mediated through the induction of the helix-loop-helix transcriptional regulators Id1 and Id2. Pharmacological inhibition of mTOR activity in HC11 mammary epithelial cells reduced cellular proliferation and prevented the lactogenic hormone-induced expression of milk proteins. Treatment of female mice with rapamycin impaired mammary gland differentiation and milk protein synthesis. The effects of mTOR on proliferation and differentiation require the functions of the helix-loop-helix proteins Id1 and Id2. Rapamycin treatment of HC11 cells resulted in a suppression of Id1 expression and an inhibition of proliferation. This effect of rapamycin was reversed by the forced expression of Id1. Rapamycin also prevented the induction of Id2 by lactogenic hormones and milk protein gene expression. Expression of a Id2 transgene bypassed the requirement of mTOR activity for beta-casein induction. These data suggest that mTOR activity has distinguishable functions in the proliferative and the differentiated state of mammary epithelial cells: it is a prerequisite for proliferation through the induction of Id1 and for differentiation-specific gene expression through the induction of Id2. The relative strengths of these proliferation and differentiation signals reflected by the expression levels of the individual Id proteins are crucial to the functional life cycle of mammary epithelial cells and might be disturbed in tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Regulates the Growth of Mammary Epithelial Cells through the Inhibitor of Deoxyribonucleic Acid Binding Id1 and Their Functional Differentiation through Id2

Jankiewicz

Groner

Desrivières

2006

Molecular Endocrinology

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“…The morphology of the mammary glands was examined using the whole-mount technique (25). Glands were spread on glass slides, fixed, and subjected to carmine (Sigma Chemicals) staining.…”

Section: Whole Mounts Tissue Histology and Immunohistochemistrymentioning

confidence: 99%

A Humanized Pattern of Aromatase Expression Is Associated with Mammary Hyperplasia in Mice

Zhao¹,

Pearson²,

Brooks³

et al. 2012

Endocrinology

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Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Arom(hum) mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast adipose fibroblasts and myoepithelial cells. Estrogen levels in the breast tissue of Arom(hum) mice were higher than in wild-type mice, whereas circulating levels were similar. Arom(hum) mice exhibited accelerated mammary duct elongation at puberty and an increased incidence of lobuloalveolar breast hyperplasia associated with increased signal transducer and activator of transcription-5 phosphorylation at 24 and 64 wk. Hyperplastic epithelial cells showed remarkably increased proliferative activity. Thus, we demonstrated that the human aromatase gene can be expressed via its native promoters in a wide variety of mouse tissues and in a distribution pattern nearly identical to that of humans. Locally increased tissue levels, but not circulating levels, of estrogen appeared to exert hyperplastic effects on the mammary gland. This novel mouse model will be valuable for developing tissue-specific aromatase inhibition strategies.

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“…Total RNAs from cells (20 lg) were separated by denaturing formaldehyde electrophoresis, transferred to a nylon membrane by capillary action overnight, and hybridized as previously described [24,25]. The b subunit probes for rat FSH and LH were generated by RT-PCR using the following primers: rat Fshb sense, 5 0 -ATCTGGTGTATAAGGACCCA-3 0 ; rat Fshb antisense, 5 0 -TCATTTCACTGAAGGAGCAG-3 0 ; rat Lhb sense, 5 0 -ATGCTCCAGG GACTGCTGCT-3 0 ; rat Lhb antisense, 5 0 -GCAGCTTGAGAAGTCTTTAT-3 0 .…”

Section: Northern Blotmentioning

confidence: 99%

Metformin Decreases GnRH- and Activin-Induced Gonadotropin Secretion in Rat Pituitary Cells: Potential Involvement of Adenosine 5' Monophosphate-Activated Protein Kinase (PRKA)

Tosca

Froment

Ramé

et al. 2010

Biology of Reproduction

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Metformin is an insulin sensitizer molecule used for the treatment of infertility in women with polycystic ovary syndrome and insulin resistance. It modulates the reproductive axis, affecting the release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). However, metformin's mechanism of action in pituitary gonadotropin-secreting cells remains unclear. Adenosine 5' monophosphate-activated protein kinase (PRKA) is involved in metformin action in various cell types. Here, we investigated the effects of metformin on gonadotropin secretion in response to activin and GnRH in primary rat pituitary cells (PRP), and studied PRKA in rat pituitary. In PRP, metformin (10 mM) reduced LH and follicle-stimulating hormone (FSH) secretion induced by GnRH (10(-8) M, 3 h), FSH secretion, and mRNA FSHbeta subunit expression induced by activin (10(-8) M, 12 or 24 h). The different subunits of PRKA are expressed in pituitary. In particular, PRKAA1 is detected mainly in gonadotrophs and thyrotrophs, is less abundant in lactotrophs and somatotrophs, and is undetectable in corticotrophs. In PRP, metformin increased phosphorylation of both PRKA and acetyl-CoA carboxylase. Metformin decreased activin-induced SMAD2 phosphorylation and GnRH-induced mitogen-activated protein kinase (MAPK) 3/1 (ERK1/2) phosphorylation. The PRKA inhibitor compound C abolished the effects of metformin on gonadotropin release induced by GnRH and on FSH secretion and Fshb mRNA induced by activin. The adenovirus-mediated production of dominant negative PRKA abolished the effects of metformin on the FSHbeta subunit mRNA and SMAD2 phosphorylation induced by activin and on the MAPK3/1 phosphorylation induced by GnRH. Thus, in rat pituitary cells, metformin decreases gonadotropin secretion and MAPK3/1 phosphorylation induced by GnRH and FSH release, FSHbeta subunit expression, and SMAD2 phosphorylation induced by activin through PRKA activation.

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PTEN overexpression suppresses proliferation and differentiation and enhances apoptosis of the mouse mammary epithelium

Cited by 83 publications

References 53 publications

Mammalian Target of Rapamycin Regulates the Growth of Mammary Epithelial Cells through the Inhibitor of Deoxyribonucleic Acid Binding Id1 and Their Functional Differentiation through Id2

Mammalian Target of Rapamycin Regulates the Growth of Mammary Epithelial Cells through the Inhibitor of Deoxyribonucleic Acid Binding Id1 and Their Functional Differentiation through Id2

A Humanized Pattern of Aromatase Expression Is Associated with Mammary Hyperplasia in Mice

Metformin Decreases GnRH- and Activin-Induced Gonadotropin Secretion in Rat Pituitary Cells: Potential Involvement of Adenosine 5' Monophosphate-Activated Protein Kinase (PRKA)

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