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Fendrick, James L.; Raafat, Ahmed; Haslam, Sandra Z.

doi:10.1023/a:1018766000275

Cited by 126 publications

(25 citation statements)

References 79 publications

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“…Endocrine ablation and gene knockout studies have shown that neither hormone alone is sufficient, and PRKO and PRL receptor knockout (PRLRKO) mice exhibit a similar phenotype suggesting crosstalk between P4 and PRL signaling pathways (Barash, 2006; Bole-Feysot et al, 1998; Brisken and Rajaram, 2006; Fendrick et al, 1998; Goff in and Kelly, 1997; Hennighausen and Robinson, 2008). Gene microarray analysis of mammary glands of ovariectomized adult mice identified a subset of genes unregulated by P4 (Fernandez -Valdivia et al, 2008) that were also down regulated in a microarray analysis of PRL receptor knock out mice, and thus were considered candidate PRL unregulated targets (Gass et al, 2003; Harris et al, 2006).…”

Section: Crosstalk Between Prolactin/stat5 and Progesterone/pr Sigmentioning

confidence: 99%

The biology of progesterone receptor in the normal mammary gland and in breast cancer

Obr

Edwards

2012

Molecular and Cellular Endocrinology

147

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This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies have led to the concept that progesterone controls proliferation and morphogenesis of the luminal epithelium in a tightly orchestrated manner at distinct stages of development by paracrine signaling pathways, including receptor of activated nuclear factor κ ligand (RANKL) as a major paracrine factor. Progesterone also drives expansion of stem cells by paracrine signals to generate progenitors required for alveologenesis. During mid-to-late pregnancy, progesterone has another role to suppress secretory activation until parturition mediated in part by crosstalk between PR and prolactin/Stat5 signaling to inhibit induction of milk protein gene expression, and by inhibiting tight junction closure. In models of hormone-dependent mouse mammary tumors, the progesterone/PR signaling axis enhances pre-neoplastic progression by a switch from a paracrine to an autocrine mode of proliferation and dysregulation of the RANKL signaling pathway. Limited experiments with normal human breast show that progesterone/PR signaling also stimulates epithelial cell proliferation by a paracrine mechanism; however, the signaling pathways and whether RANKL is a major mediator remains unknown. Work with human breast cancer cell lines, patient tumor samples and clinical studies indicates that progesterone is a risk factor for breast cancer and that alteration in progesterone/PR signaling pathways contributes to early stage human breast cancer progression. However, loss of PR expression in primary tumors is associated with a less differentiated more invasive phenotype and worse prognosis, suggesting that PR may limit later stages of tumor progression.

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Section: Crosstalk Between Prolactin/stat5 and Progesterone/pr Sigmentioning

confidence: 99%

The biology of progesterone receptor in the normal mammary gland and in breast cancer

Obr

Edwards

2012

Molecular and Cellular Endocrinology

147

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“…The strongest support for this idea is that proliferation in the mammary gland occurs during the luteal phase of the estrus cycle when progesterone levels are high (17). A clear distinction has to be made between lobular growth, which is progesterone-mediated, and ductal growth, which is E 2 -mediated (21)(22)(23). During the estrus cycle and in preparation for pregnancy, it is lobular growth that occurs (17).…”

mentioning

confidence: 99%

Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland

Cheng

Zhang

Warner

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

110

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Most evidence supports the view that ERα is responsible for estrogen (ovarian estradiol, E 2 )-induced proliferation in the epithelial cells of the mammary gland, but despite this, proliferating epithelial cells do not express ERα. We have examined this apparent paradox by studying the role of ERα and ERβ in E 2 -induced proliferation in mammary glands (measured by BrdUrd incorporation into DNA) in mice with intact ERβ (WT mice) and those in which the ERβ gene has been inactivated (ERβ -/- mice). On treatment of ERβ -/- mice with E 2 or ovariectomized WT mice with E 2 , tamoxifen, or a specific ERβ agonist (BAG), the number of BrdUrd-labeled cells in mammary glands increased from 3.4% in controls to 28-38% in the treated mice. This indicates that both ERα and ERβ can mediate E 2 -induced proliferation independently of each other. With specific antibodies, ERβ was found in both epithelial and stromal cells, whereas ERα was strictly epithelial. Within 4 h of a single dose of E 2 , ERα was lost from the nuclei of epithelial cells. In WT mice, ERα reappeared by 24 h, but in ERβ -/- mice, return to the nucleus was delayed by 24 h. At 4 h after E 2 , neither ERα nor progesterone receptor was detectable in BrdUrd-labeled nuclei but by 48 h after E 2 , 29% of the BrdUrd-labeled cells expressed ERα, and 21-38% expressed progesterone receptor. During 3 weeks of continuous E 2 treatment, ERβ remained in the nucleus, but there was no detectable ERα. With tamoxifen treatment, ERα remained in the nucleus, but ERβ was lost. From these results, we conclude that ERα receives the proliferation signal from E 2 , initiates DNA synthesis, and is then lost from cells. The subsequent steps in proliferation can proceed in the absence of either ERα or ERβ. ERβ facilitates the return of ERα to the nucleus and restores responsiveness to E 2 . By down-regulating ERβ, tamoxifen may prolong refractoriness to E 2 in mammary epithelium.

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“…The functional development and differentiation of the mammary gland occurs, however, mainly postnatally under hormonal control and is coordinated with further reproductive development. Puberty starts with a trigger from estrogen (E 2 ) and local growth factors to elongate the simple ductal tree by stimulating cell proliferation in the terminal end buds (7–9). Subsequently, fluctuating levels of progesterone (P 4 ) stimulate the process of side branching and development of alveolar buds.…”

Section: Hormone-dependent Mammary Gland Development Including Normamentioning

confidence: 99%

“…Subsequently, fluctuating levels of progesterone (P 4 ) stimulate the process of side branching and development of alveolar buds. During pregnancy, in response to P 4 and prolactin (PRL), these alveolar buds can then differentiate into functional milk producing units, alveoli (7–9). P 4 is thought to induce these changes in the mammary gland in a paracrine manner by acting on the progesterone receptor (PR)-expressing ductal epithelial cells, to stimulate the expression of growth factors that evoke proliferation of the neighboring PR-negative cells (10).…”

Section: Hormone-dependent Mammary Gland Development Including Normamentioning

confidence: 99%

“…In both humans and dogs, most mammary carcinomas are initially hormone dependent [i.e., express receptors for P 4 (PR) and E 2 (ER)]. The remaining tumors are often categorized as human epidermal growth factor 2 (HER2) positive (overexpressing HER2) or as triple-negative breast cancer (TNBC) (i.e., devoid of PR and ER and no overexpression of HER2) (1, 5, 7–9, 19). …”

Section: Hormone-dependent Mammary Gland Development Including Normamentioning

confidence: 99%

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Molecular Signaling of Progesterone, Growth Hormone, Wnt, and HER in Mammary Glands of Dogs, Rodents, and Humans: New Treatment Target Identification

2017

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Mammary tumors are the most common form of neoplasia in the bitch. Female dogs are protected when they are spayed before the first estrus cycle, but this effect readily disappears and is already absent when dogs are spayed after the second heat. As the ovaries are removed during spaying, ovarian steroids are assumed to play an essential role in tumor development. The sensitivity toward tumor development is already present during early life, which may be caused by early mutations in stem cells during the first estrus cycles. Later on in life, tumors arise that are mostly steroid-receptor positive, although a small subset of tumors overexpressing human epidermal growth factor 2 (HER2) and some lacking estrogen receptor, progesterone receptor (PR), and HER2 (triple negative) are present, as is the situation in humans. Progesterone (P4), acting through PR, is the major steroid involved in outgrowth of mammary tissue. PRs are expressed in two forms, the progesterone receptor A (PRA) and progesterone receptor B (PRB) isoforms derived from splice variants from a single gene. The dog and the whole family of canids have only a functional PRA isoform, whereas the PRB isoform, if expressed at all, is devoid of intrinsic biological activity. In human breast cancer, overexpression of the PRA isoform is related to more aggressive carcinomas making the dog a unique model to study PRA-related mammary cancer. Administration of P4 to adult dogs results in local mammary expression of growth hormone (GH) and wing less-type mouse mammary tumor virus integration site family 4 (Wnt4). Both proteins play a role in activation of mammary stem cells. In this review, we summarize what is known on P4, GH, and Wnt signaling in canine mammary cancer, how the family of HER receptors could interact with this signaling, and what this means for comparative and translational oncological aspects of human breast cancer development.

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Untitled

Cited by 126 publications

References 79 publications

The biology of progesterone receptor in the normal mammary gland and in breast cancer

The biology of progesterone receptor in the normal mammary gland and in breast cancer

Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland

Molecular Signaling of Progesterone, Growth Hormone, Wnt, and HER in Mammary Glands of Dogs, Rodents, and Humans: New Treatment Target Identification

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