PNAs: extremely active FoxA1 signal or reprogrammable endocrine resistant breast cancer makes it more aggressive

January 9, 2020 / bioun / -- recently, in a research report published in the international journal Proceedings of the National Academy of Sciences, scientists from Baylor medical college found a new mechanism through research, which may help to explain endocrine resistant breast cancer The mechanism of obtaining metastasis characteristics and the relevant research results may help scientists to develop new breast cancer therapy Image source: nephron / Wikipedia researchers point out that the extremely active FoxA1 signal may induce the whole genome reprogramming, and lead to the enhancement of cancer cells' resistance to therapy and the increase of metastasis behavior Previously, the researchers developed the extremely active FoxA1 signal in the metastatic breast cancer with endocrine resistance The researchers found that HIF-2a may be a key mediator for FoxA1 directed reprogramming, while HIF-2a inhibitors (currently used to treat advanced renal cell carcinoma and recurrent glioblastoma) can selectively reduce the metastasis of cancer cells and the invasion of endocrine resistant breast cancer cells with high FoxA1 activity Researchers Rachel Schiff said that about 75% of breast cancer carries estrogen receptor, so this kind of breast cancer is called estrogen receptor positive breast cancer (ER +), the initial ER + breast cancer cells rely on estrogen to grow, hormone therapy can make cancer cells unable to use estrogen, so that some patients' condition can be long-term relieved Tamoxifen is a kind of hormone therapy, which can play a role by binding and blocking the estrogen receptor on the surface of cancer cells However, many patients with metastatic diseases will eventually relapse, and will cause the tumor to develop acquired resistance to hormone therapy and die Such patients include those whose tumors first produced hormone therapy In a previous study, researcher Schiff and colleagues found that tumors that are more resistant to hormone therapy than susceptible cells Cells will produce more FoxA1, and the abundance of FoxA1 plays a key role in mediating the tolerance of cancer cells to therapy In this study, researchers used the whole genome method to reveal how FoxA1 can complete the complex task of cancer cell metastasis behavior When studying breast cancer cell lines in the laboratory, the researchers found that FoxA1 can reprogram breast cancer cells resistant to endocrine therapy by turning on the expression of specific genes that were previously in a closed state and turning off the expression of other genes This new gene expression mode can simulate the early embryonic development process, which can give cancer cells new functions, For example, it can migrate to other tissues and carry out malignant invasion, which is a sign that cancer cells have metastasis behavior The researchers also found that FoxA1 does not work alone When combined with other factors, it will activate a large number of enhancers, which will work together to synchronize with the whole genome cell reprogramming process HIF-2a is a top enhancer, which can work together with FoxA1 to mediate the activation of metastasis gene set and the pathway related to poor clinical prognosis Activation of When the researchers studied the cells in the laboratory, they found that the inhibitor of HIF-2a could reduce the migration and invasiveness of endocrine resistant breast cancer cells expressing high level of FoxA1 activity In the future, researchers are expected to transfer the results of this study to clinical research After analyzing the data of clinical metastatic breast cancer, researchers found that reprogramming events are similar to those in the endocrine resistant breast cancer cell model In this study, the researchers revealed the molecular mechanism of FoxA1 inducing the metastasis behavior of endocrine resistant breast cancer cells In addition, the researchers also found the above mechanism in cancers such as prostate cancer and pancreatic cancer The researchers indicated that inhibiting the function of HIF-2a or other enhancers (which can control the expression of multiple genes in endocrine resistant breast cancer) might help Develop new and effective breast cancer treatment strategies Original sources: Xiaoyong Fu, reseal Pereira, carmine De Angelis, et al FoxA1 upregulation promotions enhancer and transcribing reprogramming in endocrine resistant burst can cer, PNAs December 26, 2019 116 (52) 26823-26834; first published December 11, 2019 doi: 10.1073/pnas.1911584116