Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer.

Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets revealed that proteasome subunit transcript levels are elevated in all intrinsic subtypes (luminal, HER2-enriched, and basal-like/triple-negative) when compared to normal breast tissue.

Breast Cancer and Prolactin - New Mechanisms and Models.

The pathogenesis of breast cancer is driven by multiple hormones and growth factors. One of these, prolactin (PRL), contributes to both mammary differentiation and oncogenesis, and yet the basis for these disparate effects has remained unclear. The focus of this review is to examine and place into context 2 recent studies that have provided insight into the roles of PRL receptors and PRL in tumorigenesis and tumor progression.

Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer.

In breast cancer, prolactin-induced activation of the transcription factor STAT5a results from the phosphorylation of STAT5a tyrosine residue 694. However, its role in mammary oncogenesis remains an unsettled debate as STAT5a exhibits functional dichotomy with both pro-differentiative and pro-proliferative target genes. Phosphorylation of STAT5a serine residues, S726 and S780, may regulate STAT5a in such a way to underlie this duality.

The human intermediate prolactin receptor is a mammary proto-oncogene.

The hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr.

Breast cancer liver metastasis: current and future treatment approaches.

Nearly all fatalities arising from breast tumors are attributable to distant metastases. Breast cancer liver metastasis (BCLM) is associated with poor prognoses, with the median survival time being 2 to 3 years. Tumor intrinsic subtype directs preferential metastasis to specific organs, with HER2-enriched tumors demonstrating the highest rates of metastasis to the liver, though all subtypes can grow in the liver.

Prolactin Drives a Dynamic STAT5A/HDAC6/HMGN2 Cis-Regulatory Landscape Exploitable in ER+ Breast Cancer.

The hormone prolactin has been implicated in breast cancer pathogenesis and regulates chromatin engagement by the transcription factor, STAT5A. STAT5A is known to inducibly bind promoters and cis-regulatory elements genome-wide, though the mechanisms by which it exerts specificity and regulation of target gene expression remain enigmatic. We previously identified HDAC6 and HMGN2 as cofactors that facilitate prolactin-induced, STAT5A-mediated gene expression.

Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases.

Prolactin (PRL) and its receptor (PRLr) play important roles in the pathogenesis of breast cancer. Cyclophilin A (CypA) is a peptidyl-prolyl isomerase (PPI) that is constitutively associated with the PRLr and facilitates the activation of the tyrosine kinase Jak2. Treatment with the non-immunosuppressive prolyl isomerase inhibitor NIM811 or CypA short hairpin RNA inhibited PRL-stimulated signaling, breast cancer cell growth, and migration.

Circulating prolactin concentrations and risk of type 2 diabetes in US women.

Aims/hypothesis: Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental studies. However, whether circulating concentrations of prolactin are associated with risk of type 2 diabetes remains uncertain.

Methods: We analysed the prospective relationship between circulating prolactin concentrations and type 2 diabetes risk in the Nurses' Health Study (NHS) and NHSII with up to 22 years of follow-up.

Cyclophilin A Function in Mammary Epithelium Impacts Jak2/Stat5 Signaling, Morphogenesis, Differentiation, and Tumorigenesis in the Mammary Gland.

The prolyl isomerase cyclophilin A (CypA) regulates the Jak2/Stat5 pathway, which is necessary for mammary differentiation and the pathogenesis of breast cancer. In this study, we assessed the role of this isomerase during mammary gland development and erbB2-driven tumorigenesis. Genetic deletion of CypA resulted in delayed mammary gland morphogenesis and differentiation with corresponding decrease in Jak2/Stat5 activation; mammary gland cross-transplantation confirmed this defect was epithelial in nature.

Evaluating Nonclinical Performance of the Academic Pathologist: A Comprehensive, Scalable, and Flexible System for Leadership Use.

Academic pathologists perform clinical duties, as well as valuable nonclinical activities. Nonclinical activities may consist of research, teaching, and administrative management among many other important tasks. While clinical duties have many clear metrics to measure productivity, like the relative value units of Medicare reimbursement, nonclinical performance is often difficult to measure.

Aberrantly high expression of the CUB and zona pellucida-like domain-containing protein 1 (CUZD1) in mammary epithelium leads to breast tumorigenesis.

The peptide hormone prolactin (PRL) and certain members of the epidermal growth factor (EGF) family play central roles in mammary gland development and physiology, and their dysregulation has been implicated in mammary tumorigenesis. Our recent studies have revealed that the CUB and zona pellucida-like domain-containing protein 1 (CUZD1) is a critical factor for PRL-mediated activation of the transcription factor STAT5 in mouse mammary epithelium. Of note, CUZD1 controls production of a specific subset of the EGF family growth factors and consequent activation of their receptors.

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

The 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.

NSG Mice Provide a Better Spontaneous Model of Breast Cancer Metastasis than Athymic (Nude) Mice.

Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice.

Identification of NEK3 Kinase Threonine 165 as a Novel Regulatory Phosphorylation Site That Modulates Focal Adhesion Remodeling Necessary for Breast Cancer Cell Migration.

Accumulating evidence supports a role for prolactin (PRL) in the development and progression of human breast cancer. Although PRL is an established chemoattractant for breast cancer cells, the precise molecular mechanisms of how PRL regulates breast cancer cell motility and invasion are not fully understood. PRL activates the serine/threonine kinase NEK3, which was reported to enhance breast cancer cell migration, invasion, and the actin cytoskeletal reorganization necessary for these processes.

HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth.

Unlabelled: 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.

Engineering synthetic antibody binders for allosteric inhibition of prolactin receptor signaling.

Background: Many receptors function by binding to multiple ligands, each eliciting a distinct biological output. The extracellular domain of the human prolactin receptor (hPRL-R) uses an identical epitope to bind to both prolactin (hPRL) and growth hormone (hGH), yet little is known about how each hormone binding event triggers the appropriate response.

Findings: Here, we utilized a phage display library to generate synthetic antibodies (sABs) that preferentially modulate hPRL-R function in a hormone-dependent fashion.

Immunoassay and Nb2 lymphoma bioassay prolactin levels and mammographic density in premenopausal and postmenopausal women the Nurses' Health Studies.

Higher circulating prolactin levels have been associated with higher percent mammographic density among postmenopausal women in some, but not all studies. However, few studies have examined associations with dense area and non-dense breast area breast or considered associations with prolactin Nb2 lymphoma cell bioassay levels. We conducted a cross-sectional study among 1,124 premenopausal and 890 postmenopausal women who were controls in breast cancer case-control studies nested in the Nurses' Health Study (NHS) and NHSII.

Bioactive prolactin levels and risk of breast cancer: a nested case-control study.

Background: Prolactin is a lactogenic hormone associated with breast cancer risk in prospective studies, which used immunoassays. The immunoassay captures multiple isoforms and may not fully reflect the biologic activity of prolactin relevant to breast carcinogenesis.

Methods: We considered plasma bioactive prolactin levels measured by the Nb2 lymphoma cell bioassay, which is sensitive to the somatolactogenic activity of prolactin and growth hormone, within a nested case-control study of invasive breast cancer in the Nurses' Health Studies (NHS/NHSII).

Antipsychotic treatment in breast cancer patients.

Special consideration is required when prescribing antipsychotic drugs for patients with an existing diagnosis of breast cancer. The package inserts of all approved antipsychotics contain precautions regarding their administration in this patient group. These drugs are well known to elevate serum prolactin levels to varying degrees.

Comment on "Progesterone/RANKL is a major regulatory axis in the human breast".

In vivo menstrual cycle data support the findings by Tanos et al. that progesterone regulates RANKL in an ex vivo microstructure model of the human breast, but dispute the suppression of estradiol on progesterone-stimulated RANKL expression. RANKL responds to progesterone in a three-dimensional organoid culture model under conditions mimicking luteal-phase hormone concentration, suggesting that the microstructure may not be crucial to demonstrate progesterone responsiveness.

Hormonal determinants of nipple aspirate fluid yield among breast cancer cases and screening controls.

Background: Nipple aspiration fluid (NAF) use as a biosample is limited by the variable yield across studies. We investigated the endocrine determinants of yield in an ongoing breast cancer case-control study.

Methods: One-hundred and eighteen women yielding ≥2 μL NAF and 120 non-yielders were included; serum hormones were measured; differences in median hormones were assessed using the Wilcoxon rank-sum test.

The prolactin receptor transactivation domain is associated with steroid hormone receptor expression and malignant progression of breast cancer.

The polypeptide hormone prolactin (PRL) stimulates breast epithelial cell growth, differentiation, and motility through its cognate receptor, PRLr. PRLr is expressed in most breast cancers; however, its exact role remains elusive. Our laboratory previously described a novel mode of PRLr signaling in which Stat5a-mediated transcription is regulated through ligand-induced phosphorylation of the PRLr transactivation domain (TAD).

Induction of multidrug resistance transporter ABCG2 by prolactin in human breast cancer cells.

The multidrug transporter, breast cancer resistance protein, ABCG2, is up-regulated in certain chemoresistant cancer cells and in the mammary gland during lactation. We investigated the role of the lactogenic hormone prolactin (PRL) in the regulation of ABCG2. PRL dose-dependently induced ABCG2 expression in T-47D human breast cancer cells.

A humanized pattern of aromatase expression is associated with mammary hyperplasia in mice.

Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology.