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Hormone Signaling Pathways in the Postnatal Mammary Gland

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Tissue-Specific Cell Signaling

Abstract

The mammary gland is an organ that in female mammals develops after birth and specializes to produce milk to feed the offspring. The mammary gland undergoes continued remodeling in response to hormonal cues that direct its development and function throughout sexual development and reproductive age. This gland can undergo numerous cycles of proliferation, differentiation and apoptosis after each pregnancy. This is accomplished by mammary stem cells (MaSCs) capable of sustaining continuous remodeling of the mammary tissue. The biological processes that regulate mammary morphogenesis and remodeling are regulated by steroid and peptide hormones which tightly control gene expression and epigenetic changes. This chapter aims to give a general overview of the main hormones and signaling pathways that control the female mammary gland differentiation leading to a fully functional milk producing gland. For this purpose, a summary of findings from commonly used cell and animal models, as well as humans was selected to explain the effects exerted by the main hormones implicated in mammary gland biology.

F. L. Monteiro and I. Direito—Contributed equally.

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Abbreviations

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

ATG:

Autophagy protein

AR:

Androgen receptor

AREG:

Amphiregulin

BCL-2:

Bcl2-associated agonist of cell death

BEC1:

Beclin-1

BiP:

EnR stressor sensor-binding immunoglobulin protein

BM:

Basement membrane

BMI1:

Polycomb complex protein BMI-1

BMP4:

Bone morphogenetic protein 4

BTC:

Betacellulin

CCND1:

Cyclin D1

CDK6:

Cyclin-dependent kinase-6

CHOP:

DNA damage-inducible transcript 3 protein

CSN1S1:

Alpha-S1-casein

CXCR4:

C-X-C chemokine receptor type 4

CXCL12:

Stromal cell-derived factor 1

DNMTs:

DNA methyltransferases

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

EZH2:

Histone-lysine N-methyltransferase EZH2

EIF5:

Eukaryotic translation initiation factor 5A-1

ELF5:

ETS-related transcription factor Elf-5

EMT:

Epithelial mesenchymal transition

EPGN:

Epigen

EPR:

Epiregulin

ER:

Estrogen receptor

Esr:

Estrogen receptor gene

FGFs:

Fibroblast growth factors

FGFRs:

FGF receptors

FOXP3:

Forkhead box protein P3

FTO:

Alpha-ketoglutarate-dependent dioxygenase FTO

GH:

Growth hormone

GR:

Glucocorticoid receptor

GREs:

Glucocorticoid responsive elements

HB-EGF:

Heparin binding-EGF

HDMTs:

Demethylases

HMTs:

Histone methyltransferases

HOXA1:

Homeobox protein Hox-A1

HOXB3:

Homeobox protein Hox-B3

HOXD10:

Homeobox protein Hox-D10

hPTMs:

Histone post-translational modifications

hPTMs:

Histones post-translational modifications

IRE1α:

Inositol-requiring enzyme 1α

IGF:

Insulin -like growth factor

IGF1:

Insulin-like growth factor I

IGFBPs:

High affinity binding proteins

IGFRs:

Insulin growth factor-receptors

IGFs:

Insulin growth factors

IR:

Insulin receptor

INS:

Insulin

JNK:

Mitogen-activated protein kinase 8

JARID1B:

Lysine-specific demethylase 5B

KDMs:

K demethylases

LEF1:

Lymphoid enhancer-binding factor 1

MAP1LC3B:

Microtubule-associated proteins 1A/1B light chain 3B

MAPK:

Mitogen-activated protein kinases

MaSCs:

Mammary stem cells

ncRNAS:

Non-coding RNAs

NFE2L2:

Nuclear factor erythroid 2-related factor 2

NRG:

Neuroregulins

NOTCH3:

Neurogenic locus notch homolog protein 3

PARP:

Poly [ADP-ribose] polymerase

PPARγ:

Peroxisome proliferator-activated receptor gamma

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

PR:

Progesterone receptor

PRCs:

POLYCOMB REPRESSIVE COMPLEXES

PRL:

Prolactin

PRLHR:

Prolactin-releasing peptide receptor

PRLRs:

PRL receptors

PTHrP:

Parathyroid hormone related peptide

PYGO2:

Pygopus homolog 2

RANKL:

Tumor necrosis factor ligand superfamily member 11

REnR:

Rough endoplasmic reticulum

RSPO1:

R-spondin-1

RTKs:

Receptor tyrosine kinases

SLC2A1:

Facilitated glucose transporter member 1

STAT5A:

Signal transducer and activator of transcription 5A

SREBP1:

Sterol regulatory element-binding protein 1

TAL1:

T-cell acute lymphocytic leukemia protein 1

TCF3/4:

Transcription factor E2-alpha/4

TDGF1:

Teratocarcinoma-derived growth factor 1

TEBs:

Terminal end buds

TGFα:

Transforming growth factor alpha

TGFB1:

Transforming growth factor beta-1

TJs:

Tight junctions

TP53:

Cellular tumor antigen p53

SOX4:

Transcription factor SOX-4

SOX17:

Transcription factor SOX17

UPR:

Unfolded Protein Response

VIM:

Vimentin

XBP-1:

X-box-binding protein 1

ZEB1/2:

Zinc finger E-box-binding homeobox 1/2

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Acknowledgments

We apologize to authors whose work was not cited due to space limitations. We are thankful to Institute for Biomedicine—iBiMED (UID/BIM/04501/2013, POCI-01-0145-FEDER-007628 and UID/BIM/04501/2019) for supporting this project. iBiMED is supported by the Portuguese Foundation for Science and Technology (FCT), Compete2020 and FEDER fund. FLM and ID thank FCT for their fellowship (SFRH/BD/123821/2016 and SFRH/BD/117818/2016).

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  1. Hormones and Cancer Research Group, iBiMED—Institute of Biomedicine, University of Aveiro, Aveiro, Portugal

    Fátima L. Monteiro, Inês Direito & Luisa A. Helguero

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  1. Fátima L. Monteiro
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  2. Inês Direito
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  3. Luisa A. Helguero
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Correspondence to Luisa A. Helguero .

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  1. Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, Aveiro, Portugal

    Joana Vieira Silva

  2. Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium

    Maria João Freitas

  3. Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, Aveiro, Portugal

    Margarida Fardilha

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Monteiro, F.L., Direito, I., Helguero, L.A. (2020). Hormone Signaling Pathways in the Postnatal Mammary Gland. In: Silva, J.V., Freitas, M.J., Fardilha, M. (eds) Tissue-Specific Cell Signaling. Springer, Cham. https://doi.org/10.1007/978-3-030-44436-5_10

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