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p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients. Cancer Res; 70(21); 8446–56. ©2010 AACR.

Supplementary Figures 1-8, Tables 1-7 from High Levels of Hsp90 Cochaperone p23 Promote Tumor Progression and Poor Prognosis in Breast Cancer by Increasing Lymph Node Metastases and Drug Resistance

BackgroundStructural mentoring barriers are policies, practices, and cultural norms that collectively disadvantage marginalized groups and perpetuate disparities in mentoring. While these mentoring barriers can be found early in the training pathway, failure to address or overcome these barriers at the postdoctoral training stage has a direct impact on faculty diversity and national efforts to retain underrepresented groups in research careers.MethodsTo better understand the mentoring barriers faced by postdoctoral trainees, and possible ways to address them, a diverse sample of postdoctoral scholars (“postdocs”) from across the United States were asked to participate in focus groups to discuss their training experiences. We conducted five 90-minute focus groups with 32 biomedical postdocs, including 20 (63%) women and 15 (47%) individuals from underrepresented racial/ethnic groups (URG). Participants were well-represented across years of training, and 65% were at least somewhat likely to pursue a research-intensive faculty career, similar to previously reported national averages.ResultsA social ecological framework was used to examine both the upstream and downstream manifestations of structural mentoring barriers, as well as mentor barriers, overall. Themes were categorized on four broad levels: Individual (attitudes, beliefs, knowledge, or behaviors that inform mentoring barriers), Interpersonal (mentoring barriers arising from dyadic, peer, or network relationships), Institutional (departmental, institutional, organizational mentoring barriers), or Systemic (mentoring barriers originating from policies or broad social and cultural norms). Notable structural barriers included (1) academic politics and scientific hierarchy, (2) inequalities resulting from mentor prestige, (3) the (over) reliance on one mentor, (4) the lack of formal training for academic and non-academic careers, and (5) the lack of institutional diversity and institutional mentor training. These structural barriers foster mentoring practices and behaviors that lead to poor work-life balance, poor communication, and research career attrition. To overcome these barriers, postdocs strongly encouraged developing a network or team of mentors and recommended institutional interventions that create more comprehensive professional development, mentorship, and belonging.ConclusionsFor postdoctoral scientists, structural mentoring barriers can permeate down to institutional, interpersonal, and individual levels, impeding a successful transition to an independent research career. It has become clear that large-scale changes in mentoring must come from addressing the policies, practices, and cultural norms that perpetuate poor mentoring. This work provides strong evidence for promoting mentorship networks and cultivating a “mentoring milieu” that fosters a supportive community and a strong culture of mentorship at all levels.