Breast cancer stem cells and epithelial mesenchymal plasticity : implications for chemoresistance

Tumour heterogeneity is a key characteristic of cancer and has significant implications relating to tumour response to chemotherapy as well as patient prognosis and potential relapse. It is being increasingly accepted that tumours are clonal in origin, suggestive of a tumour arising from a deregulated or mutated cell. Cancer stem cells (CSC) possess these capabilities, and with appropriate intracellular triggers and/or signalling from extracellular environments, can purportedly differentiate to initiate tumour formation. Additionally through epithelial mesenchymal plasticity (EMP), where cells gain and maintain characteristics of both epithelial and mesenchymal cell types, epithelial-derived tumour cells have been shown to de-differentiate to acquire cancer stem attributes, which also impart chemotherapy resistance. This new paradigm places EMP centrally in the process of tumour progression and metastasis, as well as modulating drug response to current forms of chemotherapy. Furthermore, EMP and CSCs have been identified in cancers arising from different tissue types making it a possible generic therapeutic target in cancer biology. Using breast cancer (BrCa) as an example, we summarise here the current understanding of CSCs, the role of EMP in cancer biology - especially in CSCs and different molecular subtypes, and the implications this has for current and future cancer treatment strategies.

No evidence for association of ataxia-telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer

Background There is evidence that certain mutations in the double-strand break repair pathway ataxia-telangiectasia mutated gene act in a dominant-negative manner to increase the risk of breast cancer. There are also some reports to suggest that the amino acid substitution variants T2119C Ser707Pro and C3161G Pro1054Arg may be associated with breast cancer risk. We investigate the breast cancer risk associated with these two nonconservative amino acid substitution variants using a large Australian population-based case–control study. Methods The polymorphisms were genotyped in more than 1300 cases and 600 controls using 5' exonuclease assays. Case–control analyses and genotype distributions were compared by logistic regression. Results The 2119C variant was rare, occurring at frequencies of 1.4 and 1.3% in cases and controls, respectively (P = 0.8). There was no difference in genotype distribution between cases and controls (P = 0.8), and the TC genotype was not associated with increased risk of breast cancer (adjusted odds ratio = 1.08, 95% confidence interval = 0.59–1.97, P = 0.8). Similarly, the 3161G variant was no more common in cases than in controls (2.9% versus 2.2%, P = 0.2), there was no difference in genotype distribution between cases and controls (P = 0.1), and the CG genotype was not associated with an increased risk of breast cancer (adjusted odds ratio = 1.30, 95% confidence interval = 0.85–1.98, P = 0.2). This lack of evidence for an association persisted within groups defined by the family history of breast cancer or by age. Conclusion The 2119C and 3161G amino acid substitution variants are not associated with moderate or high risks of breast cancer in Australian women.

Correspondence : lymphedema following breast cancer

Lymphedema—a chronic, disabling sequela of breast cancer treatment—is finally receiving the research attention it deserves. The work published by Norman et al1 in the January issue of Journal of Clinical Oncology supports the findings of this emerging literature, which demonstrates that lymphedema is common following breast cancer treatment, but that higher estimates are observed when self-report is used to assess lymphedema status compared with other measures such as circumferences, perometry, or bio-impedance spectroscopy. While Norman et al reported that the majority of cases occur within 2 years of diagnosis, work by us2 and others3 have demonstrated that the majority of cases (70% to 80%) occur within the first 12 months after diagnosis. Collectively, this work advocates for the measurement of lymphedema being included within routine presurgical and postsurgical care. However, until we know more about the effectiveness of lymphedema treatment, clinicians may remain skeptical about active screening for lymphedema.

Does lymphedema following breast cancer warrant clinical attention?

Secondary lymphedema (swelling) after breast cancer treatment usually develops on the hand, arm, shoulder, and/or breast on the treated side. It is commonly associated with the presence of other upper-body symptoms, such as pain and aching1; it impacts physical and psychosocial functioning and adversely influences quality of life.2 Moreover, it is considered incurable, progressive, and difficult to treat. Arguably, lymphedema is the most problematic and dreaded treatment-related complication of breast cancer.3