Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo- and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen-resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2-expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2-dependent activation of Wnt signalling in cancer stem/progenitor cells.

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There is increasing evidence that breast cancers contain tumor-initiating cells with stem cell properties. The importance of estrogen in the development of the mammary gland and in breast cancer is well known, but the influence of estrogen on the stem cell population has not been assessed. We

Increased cancer stem cell content during development of resistance to tamoxifen in breast cancer is driven by multiple signals, including Sox2-dependent activation of Wnt signalling. Here, we show that Sox2 increases and estrogen reduces the expression of the transcription factor Sox9. Gain and loss of function assays indicate that Sox9 is implicated in the maintenance of human breast luminal progenitor cells. CRISPR/Cas knockout of Sox9 reduces growth of tamoxifen-resistant breast tumours in vivo. Mechanistically, Sox9 acts downstream of Sox2 to control luminal progenitor cell content and is required for expression of the cancer stem cell marker ALDH1A3 and Wnt signalling activity. Sox9 is elevated in breast cancer patients after endocrine therapy failure. This new regulatory axis highlights the relevance of SOX family transcription factors as potential therapeutic targets in breast cancer.

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At Kamoto and in other Katangan deposits, copper and cobalt occur as sulfides (mostly digenite, chalcocite, bornite and carrollite) in two stratiform orebodies. The host rock is dolostone, chert and shale. There is no metamorphism. Mineralization was emplaced before major tectonic deformation.The two stratiform orebodies are separated by a barren interval. The lower one rests a few feet above an erosional surface which developed over consolidated red dolostone beds completely devoid of sulfides. Above the upper orebody, a sulfide fraction is present, consisting mostly of pyrite with some chalcopyrite.The mineralized sedimentary rocks present some of the features commonly observed in tidal-flat sediments. However, they have undergone a complex sequence of diagenetic transformations. Several authigenic (or partly authigenic) minerals have crystallized: dolomite, perhaps in part from hydromagnesite + CaC03; magnesite, from the remaining hydromagnesite; quartz; chlorite and other phyllosilicates; colorless tourmaline; pyrite; other sulfides: chalcopyrite, bornite, digenite, chalcocite, carrollite, etc ... New evidence is presented to show that this diagenesis took place at first in an environment devoid of copper and cobalt and then proceeded while the metals were brought in from an outside source.The features described may have resulted from a reaction between a hypersaline brine (with high pH and high Eh) flowing through the lower part of the Kamoto Dolostone, and a modified connate water (reducing and less alkaline because of abundant organic matter) present in the upper part.

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