Aromatase inhibitor specific metastasis is driven by the steroid receptor coactivator SRC-1

Introduction Breast cancer is the second most common cancer in women worldwide. Approximately 80% of breast cancer patients are postmenopausal women and about two thirds of those are diagnosed with hormone receptor positive breast cancer. Therefore, endocrine therapy to block ER activity and signaling is the most successful and most commonly used therapy. Aromatase Inhibitors (Als) are currently one of the most promising treatments for estrogen-receptor positive breast cancer in postmenopausal women. Even though many women initially respond to the treatment, approximately 40% will acquire resistance and relapse within 5 year. The mechanisms involved in the development of resistance to Als however are poorly understood as long-term follow up is only now becoming available. It is though that the development of resistance and resulting tumour recurrence is due, at least in part, to cellular plasticity leading to a shift in the phenotype of the tumour cell from steroid dependence to steroid independence / growth factor dependence. Consequently, the resistant cancer cells may utilize steroid receptor-independent mechanisms to drive tumour progression. Aberrant expression of the p l6 0 steroid receptor coactivators SRC-1 and SRC-3 (AIB1) in patients has been associated with resistance to endocrine therapies and the development of tumour recurrence. Although initially described as a nuclear receptor coactivator protein, SRC-1 has been shown to interact with transcription factors running downstream o f an activated MAP kinase pathway. These transcription factor interactions may represent one of the consequences of growth factor pathway cross-talk described in endocrine resistance. Functional interactions between SRC-1 and the Ets family of transcription factors, Ets2 and PEA3 have previously been reported, and this relationship has been shown to be important in tumour progression and the development of metastasis in tamoxifen treated patients. Hypothesis The hypothesis of this thesis is to investigate if the steroid receptor coactivator SRC-1 plays an important role in advancing the metastatic phenotype in Aromatase Inhibitor resistance. It will be investigated if such a role is dependent on or independent of estrogen receptor signaling. Results The development of Al resistance in cell lines gave rise to a phenotype displaying an increase in motility and invasiveness along with a loss of organisation. Both the resistant cell model and Al resistant tumour samples expressed high levels of the steroid receptor coactivator SRC-1. We found that SRC-1 interacts with the transcription factor Ets to regulate Myc and MMP9 expression and that SRC-1 was required for the aggressive Al resistant phenotype. In patients treated with a first-line Al (n=89), we found that hormone receptor switching between the primary tumour and the resistant metastasis was a common feature of disease recurrence. A significant coassociation between SRC-1 and Ets2 in the nucleus of the recurrent tissue compared with the matched primary tumour was also observed (p=0.0004, n=3). We also observed an increase in Myc and MMP9 protein expression in the recurrent tissue in comparison to the matched primary tumour. Conclusion SRC-1 plays a key functional role in the mediation of an Al resistant aggressive phenotype by utilising Ets to regulate Myc and MMP9. Targeting downstream proteins of the SRC-1 signaling pathway may offer clinical potential to treat tumour recurrence

Thank you to all our manuscript reviewers in 2015

The editors of Hereditary Cancer in Clinical Practice would like to thank all our reviewers who have contributed to the journal in 2015. Without the participation of skilful reviewers, no academic journal could succeed, and we are grateful to the committed individuals who have given their time and expertise to the peer review of manuscripts for Hereditary Cancer in Clinical Practice. We look forward to your continued support in 2016

Spitzer Follow-up of Extremely Cold Brown Dwarfs Discovered by the Backyard Worlds: Planet 9 Citizen Science Project

We present Spitzer follow-up imaging of 95 candidate extremely cold brown dwarfs discovered by the Backyard Worlds: Planet 9 citizen science project, which uses visually perceived motion in multiepoch Wide-field Infrared Survey Explorer (WISE) images to identify previously unrecognized substellar neighbors to the Sun. We measure Spitzer [3.6]–[4.5] color to phototype our brown dwarf candidates, with an emphasis on pinpointing the coldest and closest Y dwarfs within our sample. The combination of WISE and Spitzer astrometry provides quantitative confirmation of the transverse motion of 75 of our discoveries. Nine of our motion-confirmed objects have best-fit linear motions larger than 1'' yr⁻¹; our fastest-moving discovery is WISEA J155349.96+693355.2 (μ ≈ 2.”15 yr⁻¹), a possible T-type subdwarf. We also report a newly discovered wide-separation (~400 au) T8 comoving companion to the white dwarf LSPM J0055+5948 (the fourth such system to be found), plus a candidate late T companion to the white dwarf LSR J0002+6357 at 5 5 projected separation (~8700 au if associated). Among our motion-confirmed targets, five have Spitzer colors most consistent with spectral type Y. Four of these five have exceptionally red Spitzer colors suggesting types of Y1 or later, adding considerably to the small sample of known objects in this especially valuable low-temperature regime. Our Y dwarf candidates begin bridging the gap between the bulk of the Y dwarf population and the coldest known brown dwarf

Spitzer Follow-up of Extremely Cold Brown Dwarfs Discovered by the Backyard Worlds: Planet 9 Citizen Science Project

We present Spitzer follow-up imaging of 95 candidate extremely cold brown dwarfs discovered by the Backyard Worlds: Planet 9 citizen science project, which uses visually perceived motion in multi-epoch WISE images to identify previously unrecognized substellar neighbors to the Sun. We measure Spitzer [3.6]-[4.5] color to phototype our brown dwarf candidates, with an emphasis on pinpointing the coldest and closest Y dwarfs within our sample. The combination of WISE and Spitzer astrometry provides quantitative confirmation of the transverse motion of 75 of our discoveries. Nine of our motion-confirmed objects have best-fit linear motions larger than 1"/yr; our fastest-moving discovery is WISEA J155349.96+693355.2 (total motion ~2.15"/yr), a possible T type subdwarf. We also report a newly discovered wide-separation (~400 AU) T8 comoving companion to the white dwarf LSPM J0055+5948 (the fourth such system to be found), plus a candidate late T companion to the white dwarf LSR J0002+6357 at 5.5' projected separation (~8,700 AU if associated). Among our motion-confirmed targets, five have Spitzer colors most consistent with spectral type Y. Four of these five have exceptionally red Spitzer colors suggesting types of Y1 or later, adding considerably to the small sample of known objects in this especially valuable low-temperature regime. Our Y dwarf candidates begin bridging the gap between the bulk of the Y dwarf population and the coldest known brown dwarf.Comment: accepted for publication in The Astrophysical Journa

The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems IV: NIRISS Aperture Masking Interferometry Performance and Lessons Learned

We present a performance analysis for the aperture masking interferometry (AMI) mode on board the James Webb Space Telescope Near Infrared Imager and Slitless Spectrograph (JWST/NIRISS). Thanks to self-calibrating observables, AMI accesses inner working angles down to and even within the classical diffraction limit. The scientific potential of this mode has recently been demonstrated by the Early Release Science (ERS) 1386 program with a deep search for close-in companions in the HIP 65426 exoplanetary system. As part of ERS 1386, we use the same dataset to explore the random, static, and calibration errors of NIRISS AMI observables. We compare the observed noise properties and achievable contrast to theoretical predictions. We explore possible sources of calibration errors, and show that differences in charge migration between the observations of HIP 65426 and point-spread function calibration stars can account for the achieved contrast curves. Lastly, we use self-calibration tests to demonstrate that with adequate calibration, NIRISS AMI can reach contrast levels of $\sim9-10$ mag. These tests lead us to observation planning recommendations and strongly motivate future studies aimed at producing sophisticated calibration strategies taking these systematic effects into account. This will unlock the unprecedented capabilities of JWST/NIRISS AMI, with sensitivity to significantly colder, lower mass exoplanets than ground-based setups at orbital separations inaccessible to JWST coronagraphy.Comment: 20 pages, 12 figures, submitted to AAS Journal

The \textit{JWST} Early Release Science Program for Direct Observations of Exoplanetary Systems III: Aperture Masking Interferometric Observations of the star HIP\,65426 at 3.8 μm\boldsymbol{3.8\,\rm{\mu m}}

We present aperture masking interferometry (AMI) observations of the star HIP 65426 at $3.8\,\rm{\mu m}$ as a part of the \textit{JWST} Direct Imaging Early Release Science (ERS) program obtained using the Near Infrared Imager and Slitless Spectrograph (NIRISS) instrument. This mode provides access to very small inner working angles (even separations slightly below the Michelson limit of ${}0.5\lambda/D$ for an interferometer), which are inaccessible with the classical inner working angles of the \textit{JWST} coronagraphs. When combined with \textit{JWST}'s unprecedented infrared sensitivity, this mode has the potential to probe a new portion of parameter space across a wide array of astronomical observations. Using this mode, we are able to achieve a contrast of $\Delta m_{F380M}{\sim }7.8$\,mag relative to the host star at a separation of {\sim}0.07\arcsec but detect no additional companions interior to the known companion HIP\,65426\,b. Our observations thus rule out companions more massive than 10{-}12\,\rm{M\textsubscript{Jup}} at separations ${\sim}10{-}20\,\rm{au}$ from HIP\,65426, a region out of reach of ground or space-based coronagraphic imaging. These observations confirm that the AMI mode on \textit{JWST} is sensitive to planetary mass companions orbiting at the water frost line, even for more distant stars at $\sim$100\,pc. This result will allow the planning and successful execution of future observations to probe the inner regions of nearby stellar systems, opening essentially unexplored parameter space.Comment: 15 pages, 9 figures, submitted to ApJ Letter