Table Of ContentAdvances in Experimental Medicine and Biology
Volume 846
Series Editors
Irun R. Cohen
The Weizmann Institute of Science, Rehovot, Israel
N.S. Abel Lajtha
Kline Institute for Psychiatric Research, Orangeburg, New York, USA
Rodolfo Paoletti
University of Milan, Milan, Italy
John D. Lambris
University Of Pennsylvania, Philadelphia, Pennsylvania, USA
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Maria Diakonova
Editor
Recent Advances in Prolactin
Research
1 3
Editor
Maria Diakonova
Department of Biological Sciences
University of Toledo
Toledo
Ohio
USA
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-3-319-12113-0 ISBN 978-3-319-12114-7 (eBook)
DOI 10.1007/978-3-319-12114-7
Library of Congress Control Number: 2014956558
Springer Cham Heidelberg New York Dordrecht London
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Preface
This book is devoted to some aspects of the prolactin action. Although prolactin
(PRL) was discovered more than 80 years ago, our understanding of the roles of
PRL in the human physiology is still very incomplete. Thus, PRL is not only a pitu-
itary hormone with an important role in the reproduction but also acts as a cytokine,
eliciting a wide variety of actions. Data gathered during the last decade have dem-
onstrated that locally produced PRL acts as the autocrine/paracrine factor and plays
a role in breast cancer. Following the reestablishment of a contributory role for PRL
during breast oncogenesis, the scientific and clinical communities have held great
hope that manipulation of the PRL axis may lead to the successful treatment of
breast cancer. This hope is not yet dashed, however the role of the PRL axis is now
being shown to be more complex than was primary envisaged. The first aim of this
book is to overview major advances in the field.
Secondly, this book presents information on the role of PRL in non-mammary
tissues in physiological and patho-physiological conditions. About 100–300 func-
tions or targets have been identified for PRL in various species. This is true for
the prostate, the skin, the decidua, the brain, some immune cells, adipocytes, and
several others. The book discusses the role of PRL in adipocytes, immune response,
angiogenesis, as well as in prolactinomas and prostate tumorigenesis.
This book also aims to summarize current knowledge about PRL and its receptor,
plasticity of the PRL axis, PRL signaling pathways, and PRL crosstalk with other
oncogenic factors.
Overall, the goal of this book is to identify and review new experimental find-
ings that have provided further insight into the role of PRL in human physiology
and patho-physiology. Thus, this book bridges between new research results, as
published in journal articles, and a contextual literature review.
M. Diakonova
v
Contents
1 Prolactin (PRL) in Adipose Tissue: Regulation and Functions ............. 1
Nira Ben-Jonathan and Eric Hugo
2 Signaling Pathways Regulating Pituitary Lactotrope
Homeostasis and Tumorigenesis ............................................................... 37
Allyson K. Booth and Arthur Gutierrez-Hartmann
3 The Many Faces of Prolactin in Breast Cancer ....................................... 61
Wen Y Chen
4 Regulation of Blood Vessels by Prolactin and Vasoinhibins ................... 83
Carmen Clapp, Stéphanie Thebault, Yazmín Macotela,
Bibiana Moreno-Carranza, Jakob Triebel and
Gonzalo Martínez de la Escalera
5 T yrosyl Phosphorylated Serine-Threonine Kinase PAK1 is a
Novel Regulator of Prolactin-Dependent Breast Cancer Cell
Motility and Invasion ................................................................................. 97
Alan Hammer and Maria Diakonova
6 Plasticity of the Prolactin (PRL) Axis: Mechanisms
Underlying Regulation of Output in Female Mice ................................ 139
P. R. Le Tissier, D. J. Hodson, A. O. Martin,
N. Romanò and P. Mollard
7 Role of Src Family Kinases in Prolactin Signaling ............................... 163
Jorge Martín-Pérez, José Manuel García-Martínez,
María Pilar Sánchez-Bailón, Víctor Mayoral-Varo
and Annarica Calcabrini
8 Prolactin-Induced Protein in Breast Cancer ......................................... 189
Ali Naderi
vii
viii Contents
9 Modeling Prolactin Actions in Breast Cancer
In Vivo: Insights from the NRL-PRL Mouse ........................................ 201
Kathleen A. O’Leary, Michael P. Shea and Linda A. Schuler
10 Prolactin-Induced Prostate Tumorigenesis ............................................ 221
Lucila Sackmann-Sala and Vincent Goffin
11 Prolactin in Inflammatory Response ...................................................... 243
Ana Laura Pereira Suarez, Gonzalo López-Rincón,
Priscila A. Martínez Neri and Ciro Estrada-Chávez
12 A Positive Feedback Loop Between Prolactin and STAT5
Promotes Angiogenesis ............................................................................. 265
Xinhai Yang and Andreas Friedl
Index ................................................................................................................ 281
Chapter 1
Prolactin (PRL) in Adipose Tissue: Regulation
and Functions
Nira Ben-Jonathan and Eric Hugo
Abstract New information concerning the effects of prolactin (PRL) on metabolic
processes warrants reevaluation of its overall metabolic actions. PRL affects meta-
bolic homeostasis by regulating key enzymes and transporters associated with glu-
cose and lipid metabolism in several target organs. In the lactating mammary gland,
PRL increases the production of milk proteins, lactose, and lipids. In adipose tissue,
PRL generally suppresses lipid storage and adipokine release and affect adipogen-
esis. A specific case is made for PRL in the human breast and adipose tissues, where
it acts as a circulating hormone and an autocrine/paracrine factor. Although its over-
all effects on body composition are both modest and species-specific, PRL may be
involved in the manifestation of insulin resistance.
1.1 Introduction
Metabolic homeostasis of an individual is finely regulated by the nutritional status,
energy expenditure, and hormonal signals. Peripheral organs such as the pancreas,
liver, and adipose tissue, as well as many centers within the brain, respond to these
changes and act coordinately to maintain metabolic stability. Prolactin (PRL) is a
multifunctional pituitary hormone with more actions than all other pituitary hor-
mones combined. These functions are broadly classified as reproductive, metabolic,
osmoregulatory, and immunoregulatory. The actions of PRL are mediated by the
PRL receptor (PRLR), which is expressed in all organs associated with metabolic
regulation. Unique to humans, PRL is also produced at multiple extrapituitary sites,
N. Ben-Jonathan () · E. Hugo
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45255, USA
e-mail: [email protected]
E. Hugo
e-mail: [email protected]
© Springer International Publishing Switzerland 2015 1
M. Diakonova (ed.), Recent Advances in Prolactin Research, Advances
in Experimental Medicine and Biology 846, DOI 10.1007/978-3-319-12114-7_1
2 N. Ben-Jonathan and E. Hugo
categorizing it as a classical circulating hormone as well as an autocrine/paracrine
cytokine.
Whereas humans are the one species we wish to know most about, they are also
the least accessible to experimental manipulations. Although some properties of
PRL in humans are well documented, for example, the effects of drugs, prolacti-
noma formation, and variants of PRL and the PRLR, others remain obscure. By
necessity, then, information derived from laboratory animals is essential for the un-
derstanding of PRL in human health and disease. Nonetheless, extrapolation from
data obtained with rodents to humans should be done selectively and judiciously.
Given that both PRL homeostasis and adipose tissue properties differ greatly among
species, each section in this chapter contains an extensive comparison of these pa-
rameters in humans vs. rodents. To fully evaluate the role of PRL as a metabolic
hormone with a focus on adipose tissue, the following topics are covered: (1) char-
acteristics of PRL, (2) selected features of the PRLR, (3) adipose tissue properties,
(4) expression and regulation of adipocyte PRL, and (5) metabolic actions of PRL.
1.2 Characteristics of PRL and Lactogens
1.2.1 General Features of Lactogens
Human PRL (hRPL), growth hormone (hGH), and placental lactogen (hPL), com-
monly referred to as lactogens, are members of the cytokine superfamily which
includes over 20 proteins. Members of this family are defined by two criteria: (1)
a tertiary structure of four antiparallel α helices in an up–up–down–down configu-
ration (Fig. 1.1), and (2) binding to a nontyrosine kinase, single-pass transmem-
brane receptor [1]. Lactogens are made of a single polypeptide chain of 190–200
residues with 2–3 disulfide bridges. hPRL has three disulfide bridges, while hGH
and hPL lack the N-terminal disulfide loop. hGH and hPL share 85 % sequence
homology, but only 21–22 % homology with hPRL. In spite of the low homology at
the primary amino acid sequence, the three-dimensional topology of the three hu-
man lactogens enables their binding to the hPRLR, as discussed below. Figure 1.1
also demonstrates that all three lactogens equally stimulate proliferation of Nb2 rat
lymphocytes.
1.2.2 The PRL Protein
Humans express a single PRL gene, located on chromosome 6. In addition to the
pituitary, hPRL is independently and differentially expressed at multiple sites that
include the endometrium, myometrium, decidua, immune cells, brain, breast, pros-
tate, skin, and adipose tissue [2]. Consequently, even when pituitary PRL release
is severely impaired, humans are not deprived of locally produced PRL. As judged
