Aldehyde dehydrogenase (ALDH) 1A enzymes produce retinoic acid (RA), a transcription induction molecule. To investigate if ALDH1A1 or ALDH1A3-mediated RA signaling has an active role in breast cancer tumorigenesis, we performed gene expression and tumor xenograft studies. Analysis of breast patient tumors revealed that high levels of ALDH1A3 correlated with expression of RA-inducible genes with retinoic acid response elements (RAREs), poorer patient survival and triple-negative breast cancers. This suggests a potential link between ALDH1A3 expression and RA signaling especially in aggressive and/or triple-negative breast cancers. In MDA-MB-231, MDA-MB-468 and MDA-MB-435 cells, ALDH1A3 and RA increased expression of RA-inducible genes. Interestingly, ALDH1A3 had opposing effects in tumor xenografts, increasing tumor growth and metastasis of MDA-MB-231 and MDA-MB-435 cells, but decreasing tumor growth of MDA-MB-468 cells. Exogenous RA replaced ALDH1A3 in inducing the same opposing tumor growth and metastasis effects, suggesting that ALDH1A3 mediates these effects by promoting RA signaling. Genome expression analysis revealed that ALDH1A3 induced largely divergent gene expression in MDA-MB-231 and MDA-MB-468 cells which likely resulted in the opposing tumor growth effects. Treatment with DNA methylation inhibitor 5-aza-2'deoxycytidine restored uniform RA-inducibility of RARE-containing HOXA1 and MUC4 in MDA-MB-231 and MDA-MB-468 cells, suggesting that differences in epigenetic modifications contribute to differential ALDH1A3/RA-induced gene expression in breast cancer. In summary, ALDH1A3 induces differential RA signaling in breast cancer cells which affects the rate of breast cancer progression.

Kamin (1969) reported that after rats had been trained with one CS predicting shock, they learned virtually nothing about a second CS added to the first to form a compound—provided that the shock remained unchanged. If, however, the shock was either increased or omitted at the same time that the new CS was added, it acquired significant excitatory or inhibitory strength. Both these results were confirmed in the present experiment. In addition, however, it was found that this excitatory or inhibitory conditioning to the added element could itself be blocked if the shock remained unchanged for the first four trials after the addition of the new element. This finding implies that blocking is not due to any limitation on attentional or associative capacity, but rather occurs when subjects learn that a particular stimulus is redundant, i.e. that it predicts no change in reinforcement.

In the stochastic regime, importance of a relationship between the likelihoods of two distinct types of symmetric BTSC divisions in determining BTSC survival rates becomes apparent, consequently emphasizing the need for a set of biomarkers that are able to better characterize the BTSC hierarchy. At the large scale, we predict the importance of the aforementioned symmetric division rates in dictating brain tumour composition. Furthermore, we demonstrate possible therapeutic benefits of considering combination treatments of radiotherapy and putative BTSC inhibitors, such as bone morphogenetic proteins, while reinforcing the importance of developing novel treatment strategies that specifically target the BTSC subpopulation.

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