The “bad actor” quote comes from a recent paper by Douglas Lake and collaborators: “Expression of Quiescin Sulfhydryl Oxidase 1 is associated with a highly invasive phenotype and correlates with a poor prognosis in luminal B breast cancer”
The enzyme: readers of earlier blogs may know that Quiescin-sulfhydryl oxidases (QSOXs) catalyze disulfide bond generation within conformationally flexible peptides and proteins. In the enzymological equivalent of a “bucket brigade”, pairs of electrons are passed from the dithiol-containing substrate to molecular oxygen as shown in the Figure. In the crystal structure of the mouse QSOX1 enzyme the deep blue [Trx1] domain is handing over a pair of electrons to the green [ERV] domain prior to the final stages in catalysis (steps 3 and 4).
Breast cancer: According to the American Cancer Society, women have a 1 in 8 lifetime probability of developing breast cancer – accounting for 30% of new cancer cases among women in 2012. There are multiple categories of breast cancer: the one that Lake and colleagues were studying was luminal B breast cancer – an estrogen receptor-positive subtype.
The first paper: Lake and colleagues found that QSOX1 protein is highly over-expressed in luminal B cancers and cell lines. Knockdowns of QSOX1 protein levels suppressed cell proliferation, and dramatically reduced the invasive potential of these tumor cells. Importantly, exogenously added QSOX1 enzyme restored the invasive potential of QSOX-depleted cells. Lake and coworkers suggest that elevated QSOX levels lead to increased activity of matrix metalloproteinase 9 with a consequent stimulation of degradation of ECM components and an increased propensity for metastasis.
Lake and coworkers used the GOBO database “Gene Expression Based Outcome for Breast Cancer Online” to make the case that elevated QSOX1 message levels are associated with a poor prognosis in both luminal A and B cancers.
In a second study ” Elevated Transcription of the Gene QSOX1 Encoding Quiescin Q6 Sulfhydryl Oxidase 1 in Breast Cancer”, Soloviev et al. analyzed expressed sequence tag (EST) and serial analysis of gene expression (SAGE) databases. They also concluded that QSOX1 is highly overexpressed in some breast cancers. They used quantitative PCR to analyze a series of breast tumors, and observed a strong correlation between QSOX1 expression levels and the progression of the disease.
Other cancers: Previous posts have reported that overexpression of QSOX1 correlates with the invasive potential of prostate and pancreatic cancer tumors. In addition to modulating the activity of MMP9, what other activities of QSOX1 contribute to the increased fitness of particular tumor cells? Are these effects confined to extracellular disulfide bond regeneration/remodeling – or is the other product of QSOX catalysis – hydrogen peroxide – a factor?
But is QSOX really a “bad actor”? In a paper published in 2012, Pernodet et al. reached exactly the opposite conclusion to the studies reported above. They analyzed 217 invasive ductal carcinoma patients in their paper “High expression of QSOX1 reduces tumorogenesis, and is associated with a better outcome for breast cancer patients” Pernodet et al. found an inverse correlation between QSOX expression levels and the aggressiveness of the breast tumors they examined.
They report that “QSOX1 also reduces the invasive potential of cells by reducing cell migration and decreases the activity of the matrix metalloproteinase, MMP-2, involved in these mechanisms. Moreover, in vivo experiments show that QSOX1 drastically reduces the tumor development”
This chemist-contributor is now in a muddle! How to reconcile the differences between this work and the two studies reported at the beginning of this post – do they reflect differences in tumor populations studied? Hopefully the potential importance of these observations will encourage a more searching and comprehensive examination of the role of QSOX in tumorigenesis.
May 19th addendum to original May 8, 2013 post: for a more detailed comparison of the papers, see a recent Editorial in Breast Cancer Research by Postovit and colleagues “Illuminating luminal B: QSOX1 as a subtype-specific biomarker” [PubMed or Publisher]