Androgen Receptor Inactivation Resulted in Acceleration in Pubertal Mammary Gland Growth, Upregulation of ERα Expression, and Wnt/β-Catenin Signaling in Female Mice

Gao, Yan; Walters, Kirsty A; Desai, Reena; Zhou, Hong; Handelsman, David J.; Simanainen, Ulla

doi:10.1210/en.2014-1226

Cited by 22 publications

(15 citation statements)

References 77 publications

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“…However, in these mutants the ovaries have decreased weight and serum progesterone levels are lower confounding the interpretation of these observations. Interestingly, when the Wt AR is replaced by a mutant AR protein that cannot bind DNA, the mammary gland phenotype is quite distinct; mammary ductal branching is enhanced and cell proliferation is increased . However, serum testosterone levels are elevated in these mutants and other abnormalities of the endocrine system cannot be excluded.…”

Section: Major Hormonal Control Factors In Mammary Gland Developmentmentioning

confidence: 99%

Endocrine hormones and local signals during the development of the mouse mammary gland

Brisken

Ataca

2015

WIREs Developmental Biology

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Most of mammary gland development occurs postnatally under the control of female reproductive hormones, which in turn interact with other endocrine factors. While hormones impinge on many tissues and trigger very complex biological responses, tissue recombination experiments with hormone receptor-deficient mammary epithelia revealed eminent roles for estrogens, progesterone, and prolactin receptor (PrlR) signaling that are intrinsic to the mammary epithelium. A subset of the luminal mammary epithelial cells expresses the estrogen receptor α (ERα), the progesterone receptor (PR), and the PrlR and act as sensor cells. These cells convert the detected systemic signals into local signals that are developmental stage-dependent and may be direct, juxtacrine, or paracrine. This setup ensures that the original input is amplified and that the biological responses of multiple cell types can be coordinated. Some key mediators of hormone action have been identified such as Wnt, EGFR, IGFR, and RANK signaling. Multiple signaling pathways such as FGF, Hedgehog, and Notch signaling participate in driving different aspects of mammary gland development locally but how they link to the hormonal control remains to be elucidated. An increasing number of endocrine factors are appearing to have a role in mammary gland development, the adipose tissue is increasingly recognized to play a role in endocrine regulation, and a complex role of the immune system with multiple different cell types is being revealed. For further resources related to this article, please visit the WIREs website.

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Section: Major Hormonal Control Factors In Mammary Gland Developmentmentioning

confidence: 99%

Endocrine hormones and local signals during the development of the mouse mammary gland

Brisken

Ataca

2015

WIREs Developmental Biology

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“…Furthermore, androgen treatment in adult female monkeys reduced MEC proliferation [76]. Knockout of the Ar gene in mice results in increased ERα expression, along with an increase in MEC proliferation and fat pad invasion; both functional markers of ERα activity during puberty [77,78]. Hence, AR activity can inhibit breast development and carcinogenesis in part by antagonising ERα.…”

Section: Androgensmentioning

confidence: 99%

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

Tarulli

Laven-Law

Shakya

et al. 2015

J Mammary Gland Biol Neoplasia

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The hormone-sensing mammary epithelial cell (HS-MEC-expressing oestrogen receptor-alpha (ERα) and progesterone receptor (PGR)) is often represented as being terminally differentiated and lacking significant progenitor activity after puberty. Therefore while able to profoundly influence the proliferation and function of other MEC populations, HS-MECs are purported not to respond to sex hormone signals by engaging in significant cell proliferation during adulthood. This is a convenient and practical simplification that overshadows the sublime, and potentially critical, phenotypic plasticity found within the adult HS-MEC population. This concept is exemplified by the large proportion (~80 %) of human breast cancers expressing PGR and/or ERα, demonstrating that HS-MECs clearly proliferate in the context of breast cancer. Understanding how HS-MEC proliferation and differentiation is driven could be key to unraveling the mechanisms behind uncontrolled HS-MEC proliferation associated with ERα- and/or PGR-positive breast cancers. Herein we review evidence for the existence of a HS-MEC progenitor and the emerging plasticity of the HS-MEC population in general. This is followed by an analysis of hormones other than oestrogen and progesterone that are able to influence HS-MEC proliferation and differentiation: androgens, prolactin and transforming growth factor-beta1.

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“…AR-knock-out mice showed reluctant ductal extension and branching, as well as markedly reduced epithelial cell proliferation in the breast tissue (18), whereas transcriptional inactivation of AR in another in vivo model led to accelerated mammary growth and increased number of terminal end buds, an effect that was reversible with DHT treatment (19). Abnormal cell proliferation could be partially attributed to reduced insulin-like growth factor-1 receptor (IGF-1R) signaling via cross-talk mechanisms (impaired MAPK and cyclin D1 activation), underlining the importance of a functional AR for the physiological regulation of breast development (18,20) .…”

Section: The Androgen-ar Axis In Normal and Cancerous Breast Tissuementioning

confidence: 99%

The Role of the Androgen Receptor Signaling in Breast Malignancies

Christopoulos

Vlachogiannis

Vogkou

et al. 2017

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Abstract. Breast cancer (BrCa) is the most common malignancy among women worldwide, and one of the leading causes of cancer-related deaths in females. Despite the development of novel therapeutic modalities, triple-negative breast cancer (TNBC) remains an incurable disease. Androgen receptor (AR) is widely expressed inBreast cancer (BrCa) is the most common solid tumor among women with an annual incidence of 123 new cases/100,000 females according to the United States Cancer Statistics and 252.710 estimated new cases in the U.S. in 2017. Despite significant progress made in therapeutics during the last 2 decades, BrCa still has a poor prognosis with 5-year survival rates of metastatic disease reaching to 26% only. BrCa is the second leading cause of death among female cancers with 40,610 estimated deaths in the U.S. expected in 2017 (1).Breast cancer comprises a heterogeneous group of diseases with variable course and outcome. Currently, BrCa is subclassified into distinct molecular subtypes named: normal breast like, luminal A/B, HER-2 related, basal-like and claudinlow (2, 3). Estrogen receptor (ER), progesterone receptor (PR) and HER2 have long been established as useful prognostic and predictive biomarkers. Hormonal therapy in ER and PR positive tumors (4), as well as the use of monoclonal antibodies in HER2 over-expressing tumors (5) have shown promising results, however overall survival of metastatic disease remains relatively low (1). To date, androgen receptor (AR) has been suggested to play a key role in breast cancer biology in certain disease subgroups (6, 7).AR is expressed in all stages of breast cancer (in-situ, primary and metastatic disease) and its contribution to the progression of disease may differ depending on the stage (8). Overall, AR expression among patients with breast cancer has been estimated at approximately 77% and varies significantly among molecular subtypes of BrCa (9). Human observational studies have associated AR with better outcome in ER + tumors, but this positive effect may be lost in ER-tumors (10, 11). Of interest, AR expression correlates with better clinicopathological features in the most aggressive form of BrCa, triple-negative breast cancer (TNBC) (12). AR seems to have distinct roles in disease development and progression depending on the tumor's hormonal environment and specifically upon relative levels of androgens and estrogens.The historically used androgens together with antiandrogens, Selective AR Modulators (SARMs) and Androgen Receptor antagonists constitute valuable options for the treatment of specific disease subpopulations. In the past decade, a wealth body of studies have focused on AR targeting along with hampering major signaling pathways 6533 This Αrticle is freely accessible online.

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Androgen Receptor Inactivation Resulted in Acceleration in Pubertal Mammary Gland Growth, Upregulation of ERα Expression, and Wnt/β-Catenin Signaling in Female Mice

Cited by 22 publications

References 77 publications

Endocrine hormones and local signals during the development of the mouse mammary gland

Endocrine hormones and local signals during the development of the mouse mammary gland

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

The Role of the Androgen Receptor Signaling in Breast Malignancies

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