Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.
Variability in the response to salinity within Chloris gayana (Rhodes grass) germplasm was evaluated under field conditions, and random amplified polymorphic DNA (RAPD) markers were used to assess genetic relatedness among cultivars/accessions. RAPD analysis showed a clustering of cultivars of known relatedness: cv. Pioneer and accessions Local and Trancas (derived from an old Pioneer pasture established in saline soil) belonged to the same cluster, Katambora to another and tetraploid Boma and Callide could be further separated, Boma belonging to a fourth, distant cluster. Field experiments were laid out in two types of plots: control [with electrical conductivity of the saturation extract (EC) = 3·64 dS m−1] and saline (EC=13·10 dS m−1) and two experiments were carried out: one to evaluate the effects of salinity on emergence and establishment, and the other, with a uniform number of plants per plot, to evaluate yield under saline conditions. All cultivars/accessions had salinity‐associated decreases in dry‐matter (DM) production during the establishment phase. After this stage, 1‐year DM yield was similar in all cultivars within each salinity level and production in the saline plots was significantly lower than in controls only in cv. Callide and accession Trancas. Second‐year production in the non‐saline plots increased by 30% on average over the previous year, whereas an average 40% reduction was observed in the saline plots. Thus, salinity had a negative effect on Rhodes grass establishment and persistence. The cultivars could not be ranked unequivocally by production under saline conditions, but tetraploids Boma and Callide may be said to be less tolerant than the rest on the basis of an increased proportion of dead leaves and decreased number of stolons observed in the saline plot.
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