Hormone Action in the Mammary Gland

A woman's breast cancer risk is affected by her reproductive history. The hormonal milieu also influences the course of the disease. The female reproductive hormones, estrogens, progesterone, and prolactin, have a major impact on breast cancer and control postnatal mammary gland development. Analysis of hormone receptor mutant mouse strains combined with tissue recombination techniques and proteomics revealed that sequential activation of hormone signaling in the mammary epithelium is required for progression of morphogenesis. Hormones impinge on a subset of luminal mammary epithelial cells (MECs) that express hormone receptors and act as sensor cells translating and amplifying systemic signals into local stimuli. Proliferation is induced by paracrine mechanisms mediated by distinct factors at different stages. Tissue and stage specificity of hormonal signaling is achieved at the molecular level by different chromatin contexts and differential recruitment of coactivators and corepressors

Tumor dormancy: EMT beyond invasion and metastasis.

More than two-thirds of cancer-related deaths are attributable to metastases. In some tumor types metastasis can occur up to 20 years after diagnosis and successful treatment of the primary tumor, a phenomenon termed late recurrence. Metastases arise from disseminated tumor cells (DTCs) that leave the primary tumor early on in tumor development, either as single cells or clusters, adapt to new environments, and reduce or shut down their proliferation entering a state of dormancy for prolonged periods of time. Dormancy has been difficult to track clinically and study experimentally. Recent advances in technology and disease modeling have provided new insights into the molecular mechanisms orchestrating dormancy and the switch to a proliferative state. A new role for epithelial-mesenchymal transition (EMT) in inducing plasticity and maintaining a dormant state in several cancer models has been revealed. In this review, we summarize the major findings linking EMT to dormancy control and highlight the importance of pre-clinical models and tumor/tissue context when designing studies. Understanding of the cellular and molecular mechanisms controlling dormant DTCs is pivotal in developing new therapeutic agents that prevent distant recurrence by maintaining a dormant state

Stem cells and the stem cell niche in the breast: an integrated hormonal and developmental perspective

The mammary gland is a unique organ in that it undergoes most of its development after birth under the control of systemic hormones. Whereas in most other organs stem cells divide in response to local stimuli, to replace lost cells, in the mammary gland large numbers of cells need to be generated at specific times during puberty, estrous cycles and pregnancy to generate new tissue structures. This puts special demands on the mammary stem cells and requires coordination of local events with systemic needs. Our aim is to understand how the female reproductive hormones control mammary gland development and influence tumorigenesis. We have shown that steroid hormones act in a paracrine fashion in the mammary gland delegating different functions to locally produced factors. These in turn, affect cell-cell interactions that result in changes of cell behavior required for morphogenesis and differentiation. Here, we discuss how these hormonally regulated paracrine interactions may impinge on stem cells and the stem cell niche and how this integration of signals adds extra levels of complexity to current mammary stem cell models. We propose a model whereby the stem cell niches change depending on the developmental stages and the hormonal milieu. According to this model, repeated hormone stimulation of stem cells and their niches in the course of menstrual cycles may be an important early event in breast carcinogenesis and may explain the conundrum why breast cancer risk increases with the number of menstrual cycles experienced prior to a first pregnancy

The Complex Wind Torus and Jets of PSR B1706-44

We report on Chandra ACIS imaging of the pulsar wind nebula (PWN) of the young Vela-like PSR B1706-44, which shows the now common pattern of an equatorial wind and polar jets. The structure is particularly rich, showing a relativistically boosted termination shock, jets with strong confinement, a surrounding radio/X-ray PWN and evidence for a quasi-static `bubble nebula'. The structures trace the pulsar spin geometry and illuminate its possible relation to SNR G343.1-2.3. We also obtain improved estimates of the pulsar flux and nebular spectrum, constraining the system age and energetics.Comment: To appear in the Astrophysical Journal. 15pp, 4 figures in 7 file

DiFX2: A more flexible, efficient, robust and powerful software correlator

Software correlation, where a correlation algorithm written in a high-level language such as C++ is run on commodity computer hardware, has become increasingly attractive for small to medium sized and/or bandwidth constrained radio interferometers. In particular, many long baseline arrays (which typically have fewer than 20 elements and are restricted in observing bandwidth by costly recording hardware and media) have utilized software correlators for rapid, cost-effective correlator upgrades to allow compatibility with new, wider bandwidth recording systems and improve correlator flexibility. The DiFX correlator, made publicly available in 2007, has been a popular choice in such upgrades and is now used for production correlation by a number of observatories and research groups worldwide. Here we describe the evolution in the capabilities of the DiFX correlator over the past three years, including a number of new capabilities, substantial performance improvements, and a large amount of supporting infrastructure to ease use of the code. New capabilities include the ability to correlate a large number of phase centers in a single correlation pass, the extraction of phase calibration tones, correlation of disparate but overlapping sub-bands, the production of rapidly sampled filterbank and kurtosis data at minimal cost, and many more. The latest version of the code is at least 15% faster than the original, and in certain situations many times this value. Finally, we also present detailed test results validating the correctness of the new code.Comment: 28 pages, 9 figures, accepted for publication in PAS

The RRAT Trap: Interferometric Localization of Radio Pulses from J0628+0909

We present the first blind interferometric detection and imaging of a millisecond radio transient with an observation of transient pulsar J0628+0909. We developed a special observing mode of the Karl G. Jansky Very Large Array (VLA) to produce correlated data products (i.e., visibilities and images) on a time scale of 10 ms. Correlated data effectively produce thousands of beams on the sky that can localize sources anywhere over a wide field of view. We used this new observing mode to find and image pulses from the rotating radio transient (RRAT) J0628+0909, improving its localization by two orders of magnitude. Since the location of the RRAT was only approximately known when first observed, we searched for transients using a wide-field detection algorithm based on the bispectrum, an interferometric closure quantity. Over 16 minutes of observing, this algorithm detected one transient offset roughly 1' from its nominal location; this allowed us to image the RRAT to localize it with an accuracy of 1.6". With a priori knowledge of the RRAT location, a traditional beamforming search of the same data found two, lower significance pulses. The refined RRAT position excludes all potential multiwavelength counterparts, limiting its optical luminosity to L_i'<1.1x10^31 erg/s and excluding its association with a young, luminous neutron star.Comment: Submitted to ApJ, 7 pages, 5 figure

The Expression of Wnt4 Is Regulated by Estrogen via an Estrogen Receptor Alpha-dependent Pathway in Rat Pituitary Growth Hormone-producing Cells

Wnt signaling is important in many aspects of cell biology and development. In the mouse female reproductive tract, Wnt4, Wnt5a, and Wnt7a show differential expression during the estrus cycle, suggesting that they participate in female reproductive physiology. Although the pituitary is a major gland regulating reproduction, the molecular mechanism of Wnt signaling here is unclear. We elucidated the subcellular distribution of Wnt4 in the pituitary of estrogen-treated ovariectomized female rats. Expression of Wnt4 mRNA increased dramatically, particularly in proestrus compared with estrus and metestrus. Wnt4 protein was observed in the cytoplasm of almost all growth hormone (GH)-producing cells and in only a few thyroid-stimulating hormone β (TSHβ)-producing cells. In rat GH-producing pituitary tumor (MtT/S) cells, estrogen-induced expression of Wnt4 mRNA was completely inhibited by estrogen receptor antagonist ICI 182,780 in vitro. Thus, rat pituitary GH cells synthesize Wnt4 and this is induced by estrogen mediated via an estrogen receptor alpha-dependent pathway

Periodic Bursts of Coherent Radio Emission from an Ultracool Dwarf

We report the detection of periodic (p = 1.96 hours) bursts of extremely bright, 100% circularly polarized, coherent radio emission from the M9 dwarf TVLM 513-46546. Simultaneous photometric monitoring observations have established this periodicity to be the rotation period of the dwarf. These bursts, which were not present in previous observations of this target, confirm that ultracool dwarfs can generate persistent levels of broadband, coherent radio emission, associated with the presence of kG magnetic fields in a large-scale, stable configuration. Compact sources located at the magnetic polar regions produce highly beamed emission generated by the electron cyclotron maser instability, the same mechanism known to generate planetary coherent radio emission in our solar system. The narrow beams of radiation pass our line of sight as the dwarf rotates, producing the associated periodic bursts. The resulting radio light curves are analogous to the periodic light curves associated with pulsar radio emission highlighting TVLM 513-46546 as the prototype of a new class of transient radio source.Comment: 12 pages, 3 figures, accepted for publication in ApJ Letter

Prolactin signaling and Stat5: going their own separate ways?

Miyoshi et al. compared the role of the prolactin receptor (PrlR) and its downstream mediator, the signal transducer and activator of transcription 5 (Stat5), in mammary epithelial cells in vivo by studying PrlR(-/-) and Stat5ab(-/-) mouse mammary epithelial transplants during pregnancy. At first glance, the two mutant epithelia appear to have similar defects in the differentiation of the alveolar epithelium. However, a closer examination by Miyoshi et al. revealed defects in the epithelial architecture of the smallest ducts of Stat5ab(-/-) transplants not apparent in the PrlR(-/-) transplants, suggesting that Stat5 is more than a simple mediator of PrlR action

Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence

More than 70% of human breast cancers (BCs) are estrogen receptor α-positive (ER+). A clinical challenge of ER+ BC is that they can recur decades after initial treatments. Mechanisms governing latent disease remain elusive due to lack of adequate in vivo models. We compare intraductal xenografts of ER+ and triple-negative (TN) BC cells and demonstrate that disseminated TNBC cells proliferate similarly as TNBC cells at the primary site whereas disseminated ER+ BC cells proliferate slower, they decrease CDH1 and increase ZEB1,2 expressions, and exhibit characteristics of epithelial-mesenchymal plasticity (EMP) and dormancy. Forced E-cadherin expression overcomes ER+ BC dormancy. Cytokine signalings are enriched in more active versus inactive disseminated tumour cells, suggesting microenvironmental triggers for awakening. We conclude that intraductal xenografts model ER + BC dormancy and reveal that EMP is essential for the generation of a dormant cell state and that targeting exit from EMP has therapeutic potential