MUC4 is shown in pancreatic and ovarian cancer cells to increase tumor cell proliferation, motility, and tumorgenicity . We have been not able to examine the purpose of MUC4 in acquired resistance in clinical samples, as resistant tumors from human trials of L T or ED within the presence of HER2 positive ailment are presently unavailable; even so, these research are warranted as samples will develop into out there. In summary, this work describes a novel mucinated phenotype seen together with a shift while in the intimate crosstalk involving ER and HER2 resulting in an ER adverse HER2 optimistic tumor with reactivation of HER signaling and remedy resistance .
Upon acquiring resistance to treatment, the molecular profile of those tumors exhibits ER plasticity since it modifications its phenotype to ERnegative PR unfavorable HER2 good; the HER2 pathway is reactivated and there’s marked upregulation of numerous mucins, including MUC4. The p38 MAPK was at first identified Pim cancer like a mediator of inflammation and worry responses . Recent studies have exposed a novel function with the p38 pathway in tumor suppressing cellular responses like oncogene induced senescence, cell speak to inhibition and DNA harm responses . These findings recommend that p38 has a tumor suppressing perform. Certainly, tissue particular deletion of p38 promotes the improvement of chemicalinduced liver cancer and K rasG12V induced lung cancer in mice . Additionally, deletion of Wip1, a p38 phosphatase often amplified in human breast tumors, leads to p38 activation and reduced erbB2 and ras mediated mammary tumorigenesis in mice .
Like other MAPK pathways, the functions of p38 are mediated by its downstream substrates. A number of p38 substrates, which includes serine threonine protein kinases, transcription components and cell cycle regulators, have been identified that mediate many different p38 functions . The p38 downstream Magnolol kinase substrates contain MAPK activated kinases two and 3 , MAPK interacting protein kinase one , p38 regulated activated kinase , mitogen and tension activated protein kinases 1 and 2 , and casein kinase two . Upon phosphorylation by p38, these Ser Thr protein kinases activate substrates similar to heat shock proteins, transcription elements, translation initiation components, and proteins that regulate mRNA stability.
In the past study, we demonstrated that the capacity of p38 to mediate oncogene induced senescence and tumor suppression relies, no less than in aspect, on its downstream substrate kinase PRAK, also known as MAPK activated protein kinase 5 .