No abstract

Recent studies suggest that BET inhibitors are effective anti-cancer therapeutics. Here we show that BET inhibitors are effective against murine primary mammary tumors, but not pulmonary metastases. BRD4, a target of BET inhibitors, encodes two isoforms with opposite effects on tumor progression. To gain insights into why BET inhibition was ineffective against metastases the pro-metastatic short isoform of BRD4 was characterized using mass spectrometry and cellular fractionation. Our data show that the pro-metastatic short isoform interacts with the LINC complex and the metastasis-associated proteins RRP1B and SIPA1 at the inner face of the nuclear membrane. Furthermore, histone binding arrays revealed that the short isoform has a broader acetylated histone binding pattern relative to the long isoform. These differential biochemical and nuclear localization properties revealed in our study provide novel insights into the opposing roles of BRD4 isoforms in metastatic breast cancer progression.

Background Women and underrepresented in medicine and the health sciences (URiM) faculty face inequities in advancement. Career sponsorship may be a remedy. Few studies have described sponsorship in academic medicine and none across an institution. Objective To examine faculty awareness, experiences, and perceptions of sponsorship at a large academic health center. Design Anonymous online survey. Participants Faculty with a ≥50% appointment. Main Measures The survey contained 31 Likert, multiple-choice, yes/no, and open-ended questions about familiarity with the concept of sponsorship; experience of having or being a sponsor; receipt of specific sponsorship activities; sponsorship impact and satisfaction; mentorship and sponsorship co-occurrence; and perception of inequities. Open-ended questions were analyzed using content analysis. Key Results Thirty-one percent of the surveyed faculty (903/2900) responded of whom 53% (477/903) were women and 10% (95/903) were URiM. Familiarity with sponsorship was higher among assistant (91%, 269/894) and associate (182/894; 64%) professors versus full professors (38%, 329/894); women (67%, 319/488) versus men (62%, 169/488); and URiM (77%, 66/517) versus non-URiM faculty (55%, 451/517). A majority had a personal sponsor (528/691; 76%) during their career and were satisfied with their sponsorship (64%, 532/828). However, when responses from faculty of different professorial ranks were stratified by gender and URiM identity, we observed possible cohort effects. Furthermore, 55% (398/718) of respondents perceived that women received less sponsorship than men and 46% (312/672) that URiM faculty received less than their peers. We identified seven qualitative themes: sponsorship importance, growing awareness and change, institutional biases and deficiencies, groups getting less sponsorship, people with sponsorship power, conflation with mentorship, and potential for negative impact. Conclusions A majority of respondents at a large academic health center reported sponsorship familiarity, receipt, and satisfaction. Yet many perceived persistent institutional biases and the need for systematic change to improve sponsorship transparency, equity, and impact.