The Prolactin Receptor Transactivation Domain Is Associated with Steroid Hormone Receptor Expression and Malignant Progression of Breast Cancer

Fiorillo, Alyson A.; Medler, Terry R.; Feeney, Yvonne B.; Wetz, Suzanne M.; Tommerdahl, Kalie L.; Clevenger, Charles V.

doi:10.1016/j.ajpath.2012.09.021

Cited by 28 publications

(36 citation statements)

References 84 publications

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“…CEL files and normalized expression values (as described in Material and Methods ) were published online and are accessible via the NCBI Gene Expression Omnibus at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE81217. There was high concordance between the prolactin stimulated differential expression reported here and that previously reported by our group (39). Regarding the prolactin induced, Bufexamac inhibited expression of the prolactin receptor target genes CISH , CCND1 , and CEBPB , the microarray data was in agreement with the qPCR and immunoblot data reported elsewhere in this manuscript (Fig.…”

Section: Resultssupporting

confidence: 92%

HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth

Medler

Craig

Fiorillo

et al. 2016

Molecular Cancer Research

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Stat5a is a transcription factor utilized by several cytokine/hormone receptor signaling pathways that promotes transcription of genes associated with proliferation, differentiation, and survival of cancer cells. However, there are currently no clinically approved therapies that directly target Stat5a, despite ample evidence that it contributes to breast cancer pathogenesis. Here, deacetylation of the Stat5a coactivator and chromatin remodeling protein HMGN2 on lysine residue K2 by HDAC6 promotes Stat5a-mediated transcription and breast cancer growth. HDAC6 inhibition both in vitro and in vivo enhances HMGN2 acetylation with a concomitant reduction in Stat5a-mediated signaling, resulting in an inhibition of breast cancer growth. Furthermore, HMGN2 is highly acetylated at K2 in normal human breast tissue, but is deacetylated in primary breast tumors and lymph node metastases, suggesting that targeting HMGN2 deacetylation is a viable treatment for breast cancer. Together, these results reveal a novel mechanism by which HDAC6 activity promotes the transcription of Stat5a target genes and demonstrate utility of HDAC6 inhibition for breast cancer therapy. Implications HMGN2 deacetylation enhances Stat5a transcriptional activity, thereby regulating prolactin-induced gene transcription and breast cancer growth.

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Section: Resultssupporting

confidence: 92%

HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth

Medler

Craig

Fiorillo

et al. 2016

Molecular Cancer Research

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“…Our results suggest that the role of PRL over mammary glands may not be restricted to its known trophic effect during pregnant and lactation phases, but it also could be modulating other physiological processes in mammary glands of non-pregnant animals. In fact, it has been shown that intact transmembrane PRLR localizes in the nucleus of human breast carcinoma cells where it functions as a coactivator through interaction with the latent transcription factor Stat5a and the high mobility group N2 protein (HMGN2) and contributes to the expression of the ER and progesterone receptor (PR) [22,23].…”

Section: Cyclingmentioning

confidence: 99%

Ovarian, Hypophyseal and Hypothalamic Hormones Coordinate Mammary Gland Remodeling in Adult Lagostomus maximus: a Rodent that Shows Pseudo-Ovulation at Mid-Gestation

Halperín¹,

Dorfman²,

Vitullo³

2017

Current Topics in Lactation

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Adult female mammary glands go through extensive tissue remodeling during pregnancy, lactation and after the weaning of the neonates. Here we characterize mammary gland morphology of adult females of Lagostomus maximus, a hystricomorph rodent with a pseudo-ovulatory event at mid-gestation, and describe how the glandular tissue changes its architecture in response to variations of the hormonal environment. At mid-gestation, pseudo-ovulation is seen as an essential event increasing the number of secondary corpora lutea and thus rising the circulating levels of progesterone that help to maintain pregnancy to term. As a side effect, mammary gland development is favored early during the long-lasting pregnancy of L. maximus, preparing females for the nutritional need of fully developed pups in this k-strategist species.

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“…PRL-induced genes were previously identified by our laboratory through global RNA profiling (42,43), and the genes immediate early response 3 (IER3) and pleckstrin homologylike domain, family A, member 2 (PHLDA2) were chosen for further analysis based on their breast cancer relevance (see "Discussion"). PRL treatment resulted in increased expression of CISH, IER3, and PHLDA2 here (Fig.…”

Section: Prl Treatment Induces Chromatin Decompaction and Promotes Bimentioning

confidence: 99%

“…RNA Interference-Stable shRNA-mediated knockdown of HMGN2 via retroviral infection has been described previously (30,42), using the retroviral vector pRFP-C-RS expressing shRNA targeting HMGN2 (5Ј-GTGTCAGGCAATCTGGA-CTTTCCAGTGAT-3Ј; catalogue no. TF319505, Origene, Rockville, MD).…”

Section: Journal Of Biological Chemistry 2249mentioning

confidence: 99%

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells

Schauwecker

Kim

Licht

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuThe hormone prolactin (PRL) contributes to breast cancer pathogenesis through various signaling pathways, one of the most notable being the JAK2/signal transducer and activator of transcription 5 (STAT5) pathway. PRL-induced activation of the transcription factor STAT5 results in the up-regulation of numerous genes implicated in breast cancer pathogenesis. However, the molecular mechanisms that enable STAT5 to access the promoters of these genes are not well understood. Here, we show that PRL signaling induces chromatin decompaction at promoter DNA, corresponding with STAT5 binding. The chromatin-modifying protein high mobility group nucleosomal binding domain 2 (HMGN2) specifically promotes STAT5 accessibility at promoter DNA by facilitating the dissociation of the linker histone H1 in response to PRL. Knockdown of H1 rescues the decrease in PRL-induced transcription following HMGN2 knockdown, and it does so by allowing increased STAT5 recruitment. Moreover, H1 and STAT5 are shown to function antagonistically in regulating PRL-induced transcription as well as breast cancer cell biology. While reduced STAT5 activation results in decreased PRL-induced transcription and cell proliferation, knockdown of H1 rescues both of these effects. Taken together, we elucidate a novel mechanism whereby the linker histone H1 prevents STAT5 binding at promoter DNA, and the PRL-induced dissociation of H1 mediated by HMGN2 is necessary to allow full STAT5 recruitment and promote the biological effects of PRL signaling.In the mammary gland, signals from the polypeptide hormone prolactin (PRL) are essential for normal development (1-4), and these physiological effects are mediated through the homologous transcription factors signal transducer and activator of transcription 5a and 5b (referred to as STAT5) (5). PRL signals by binding to the PRL receptor (PRLR), 2 a transmembrane receptor of the cytokine receptor superfamily. Binding of PRL to the PRLR results in the activation of STAT5 via phosphorylation by the tyrosine kinase Janus kinase 2 (JAK2) (6 -8). Phosphorylated STAT5 dimerizes, and the active STAT5 dimers translocate to the nucleus. In the nucleus, STAT5 recognizes and binds to consensus elements in the DNA, which induces the expression of STAT5 target genes (9).PRL-induced STAT5 activation results in the up-regulation of many pro-proliferative genes (10 -12). Although essential for proper mammary gland development, aberrant PRL signaling and STAT5 activation also contribute to breast cancer pathogenesis. Transgenic mice that overexpress PRL in the mammary epithelium develop mammary tumors, which can be either estrogen receptor-positive or -negative (13). In epidemiologic studies, women with elevated serum PRL are at an increased risk of developing breast cancer (14 -17). PRL also enhances the proliferation, motility, and survival of breast cancer cells (18 -20). Similarly, overexpression of STAT5 in the mammary gland of transgenic mice results in mammary tumor development (21), whereas hemizygous los...

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The Prolactin Receptor Transactivation Domain Is Associated with Steroid Hormone Receptor Expression and Malignant Progression of Breast Cancer

Cited by 28 publications

References 84 publications

HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth

HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth

Ovarian, Hypophyseal and Hypothalamic Hormones Coordinate Mammary Gland Remodeling in Adult Lagostomus maximus: a Rodent that Shows Pseudo-Ovulation at Mid-Gestation

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells

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