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Resilience, or positive adaptation in the face of adversity, mitigates the negative effects of stress and promotes lifelong physical and mental wellbeing. Identifying adolescents who are struggling with stress could provide opportunities for individual clinical preventive interventions. However, resilience assessments are rarely performed in clinical settings and no clear, evidence-based protocols or language for such exploration exist. The aim of this qualitative study was to identify both clinically feasible methods for assessment, and actual findings, regarding stress, supports, attributes, and strategies youth consider most useful for building resilience. We recruited 59 urban and rural dwelling 13-16 year olds from two Canadian primary care practices. Interviewers asked five open-ended questions about sources of stress and resilience and wrote summaries of answers provided. These were then coded. Researchers independently identified conceptual themes, then reached consensus on these. Stress arose from schoolwork and conflicts with friends or family, rather than from socioeconomic adversities. A majority of participants felt able to manage stresses well, finding strength through (1) social connection with family or friends; (2) self-reliant activities including exercise, music or drawing; and (3) personal attributes such as optimism, calmness and competence. They used a variety of approaches to work through stress, many of which align with key domains of resilience, as well as the novel technique of distraction. Ruminating on stress-provoking events made youth feel they were coping poorly. Most participants experienced stress and drew strength from psychosocial and emotional assets, as well as external resources that fostered resilience. Direct, open conversation was particularly effective for building rapport, augmenting strengths by discussing them, and identifying those who were struggling. Similar questions asked in clinical practice may open doors to deep and, perhaps, transformative conversations and evidence-based preventive interventions.

The triple-negative breast cancer (TNBC) subtype is enriched in cancer stem cells (CSCs) and clinically correlated with the highest rate of recurrence. Several studies implicate the RSK pathway as being pivotal for the growth and proliferation of CSCs, which are postulated to drive tumor relapse. We now address the potential for the newly developed RSK inhibitor LJI308 to target the CSC population and repress TNBC growth and dissemination. Overexpression of the Y-box binding protein-1 (YB-1) oncogene in human mammary epithelial cells (HMECs) drove TNBC tumor formation characterized by a multi-drug resistance phenotype, yet these cells were sensitive to LJI308 in addition to the classic RSK inhibitors BI-D1870 and luteolin. Notably, LJI308 specifically targeted transformed cells as it had little effect on the non-tumorigenic parental HMECs. Loss of cell growth, both in 2D and 3D culture, was attributed to LJI308-induced apoptosis. We discovered CD44+/CD49f+ TNBC cells to be less sensitive to chemotherapy compared to the isogenic CD44-/CD49f- cells. However, inhibition of RSK using LJI308, BI-D1870, or luteolin was sufficient to eradicate the CSC population. We conclude that targeting RSK using specific and potent inhibitors, such as LJI308, delivers the promise of inhibiting the growth of TNBC.

Y-box binding protein-1 (YB-1) is the first reported oncogenic transcription factor to induce the tumor-initiating cell (TIC) surface marker CD44 in triple-negative breast cancer (TNBC) cells. In order for CD44 to be induced, YB-1 must be phosphorylated at S102 by p90 ribosomal S6 kinase (RSK). We therefore questioned whether RSK might be a tractable molecular target to eliminate TICs. In support of this idea, injection of MDA-MB-231 cells expressing Flag-YB-1 into mice increased tumor growth as well as enhanced CD44 expression. Despite enrichment for TICs, these cells were sensitive to RSK inhibition when treated ex vivo with BI-D1870. Targeting RSK2 with small interfering RNA (siRNA) or small molecule RSK kinase inhibitors (SL0101 and BI-D1870) blocked TNBC monolayer cell growth by ∼100%. In a diverse panel of breast tumor cell line models RSK2 siRNA predominantly targeted models of TNBC. RSK2 inhibition decreased CD44 promoter activity, CD44 mRNA, protein expression, and mammosphere formation. CD44(+) cells had higher P-RSK(S221/227) , P-YB-1(S102) , and mitotic activity relative to CD44(-) cells. Importantly, RSK2 inhibition specifically suppressed the growth of TICs and triggered cell death. Moreover, silencing RSK2 delayed tumor initiation in mice. In patients, RSK2 mRNA was associated with poor disease-free survival in a cohort of 244 women with breast cancer that had not received adjuvant treatment, and its expression was highest in the basal-like breast cancer subtype. Taking this further, we report that P-RSK(S221/227) is present in primary TNBCs and correlates with P-YB-1(S102) as well as CD44. In conclusion, RSK2 inhibition provides a novel therapeutic avenue for TNBC and holds the promise of eliminating TICs., (Copyright © 2012 AlphaMed Press.)

Tumour recurrence is one of the biggest challenges in breast cancer management because it affects 25-30% of women with breast cancer and the tumours are often incurable. Women with triple-negative breast cancer (TNBC--lacking expression of the oestrogen receptor, progesterone receptor and the receptor HER2/ERBB2) have the highest rates of early recurrence relative to other breast cancer subtypes. Early recurrence might be due to tumour-initiating cells (TICs), which are resistant to conventional therapies, can remain dormant and can subsequently give rise to secondary tumours. In breast cancer, TICs are identified by the cell-surface markers CD44+/CD24-/EpCAM+ and/or possess ALDH1 enzyme activity. This subpopulation has the ability to self-renew, grow as mammospheres and initiate tumour formation. Fuelling the problem of relapse is the fact that chemotherapy and radiation can induce or select for TICs; this was reported in preclinical models and more recently in women being treated for breast cancer. Thus, new therapeutic agents for TNBC are presently being sought to overcome this problem. Here we review the roles of receptor tyrosine kinases, signalling intermediates and transcription factors in sustaining the TIC subpopulation. Particular emphasis is placed on targeting these molecules in order to eliminate and/or prevent the induction of TICs and ultimately reduce the frequency of TNBC recurrence.