Abstract
Breast cancer is one of the most common malignancies among women which is often treated with hormone therapy and chemotherapy. Despite the improvements in detection and treatment of breast cancer, the vast majority of breast cancer patients are diagnosed with metastatic disease either at the beginning of the disease or later during treatment. Still, the molecular mechanisms causing a therapy resistant metastatic breast cancer are still elusive. In the present study we addressed the function of the transcriptional activator ZRF1 during breast cancer progression. We provide evidence that ZRF1 plays an essential role for the early metastatic events in vitro and acts like a tumor suppressor protein during the progression of breast invasive ductal carcinoma into a more advanced stage. Hence, depletion of ZRF1 results in the acquisition of metastatic behavior by facilitating the initiation of the metastatic cascade, notably for cell adhesion, migration and invasion. Furthermore absence of ZRF1 provokes endocrine resistance via misregulation of cell death and cell survival related pathways. Taken together, we have identified ZRF1 as an important regulator of breast cancer progression that holds the potential to be explored for new treatment strategies in the future.
Highlights
Breast cancer (BC) is the most frequent carcinoma in females, and the second most common cause of cancer related mortality in women
Zuotin-related factor 1 (ZRF1) knockdown MCF7 cells grew less compared to control cells, a significant difference in the growth rate was only observed at days 4 and 6
We provide evidence that ZRF1 potentially acts as a tumor suppressor protein during the progression of breast invasive ductal carcinoma into a more advanced stage
Summary
Breast cancer (BC) is the most frequent carcinoma in females, and the second most common cause of cancer related mortality in women. Tamoxifen (TAM) represents the first line treatment for both pre- and post-menopausal patients with ER (+) metastatic breast cancer It is the classic member of SERMs (selective estrogen receptor modulators), which produce both estrogenic (breast and mammary tissue) and anti-estrogenic effects (bone and uterus) at the same time depending on the respective tissue [5,6,7]. Tamoxifen is metabolized in the liver into active metabolites such as 4-hydroxytamoxifen (4-OHT) [10] Another drug used in breast cancer treatment is ICI 182,780 (ICI), a selective estrogen receptor down-regulator (SERD), a pure anti-estrogen, which can down-regulate the ER expression levels and promote its proteasomal degradation [11]. In addition to the PI3K/AKT pathway, increased expression of anti-apoptotic genes of the BCL-2 family promotes endocrine resistance by decreasing the apoptotic response towards ER-antagonists [21, 22]
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