Slug contributes to cancer progression by direct regulation of ERα signaling pathway

Abstract

Hormone therapy targeting estrogen receptor α (ERα) is the most effective treatment for breast cancer. However, this treatment eventually fails as the tumor develops resistance. Although reduced expression of ER-α is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. The present study shows that Slug has an inverse relationship with ERα in breast and prostate cancer patient samples. Also the inhibition of Slug blocks mammary stem cell activity in primary mammary epithelial cells. We hypothesize that Slug may be a key transcription factor in the regulation of ERα expression. To understand the Slug-ERα signaling pathway, we employed resistant cell line MCF-TAMR (ERα relatively negative) derived from its parental MCF-7 (ERα positive) cell line and assessed changes in cell phenotype, activity and response to therapy. Conversely, we performed knockdown of Slug in the high-Slug expressing cell line MDA-MB-231 and assessed reversal of the mesenchymal phenotype. Microarray analysis showed that Slug is overexpressed in high grade breast and prostate cancer tissues. Additionally, Slug overexpression leads to drug resistance. Furthermore, we demonstrated that Slug binds directly to ERα promoter E-boxes and represses ERα expression. This resulted in decrease in epithelial-to-mesenchymal transition in cancer cells. These findings demonstrate that Slug, by regulation of ERα expression, contributes to tumor progression and could serve as an important target for cancer therapy.

Downregulation of LAPTM5 suppresses cell proliferation and viability inducing cell cycle arrest at G0/G1 phase of bladder cancer cells

“…After re-localization from membrane to cytoplasm and nucleus, β-catenin became a transcriptional coactivator to promote EMT (24). Slug is a zinc-finger transcription factor and has a functional role in triggering EMT (25), cancer progression (26), invasion and migration (27). Consistently, our results showed that LAPTM5 knockdown resulted in an increase of E-cadherin and decrease of N-cadherin, β-catenin and Slug in BCa cells (Fig.…”

Targeting Platelets for the Treatment of Cancer

“…The presence of platelets around breast cancer primary tumour cells was associated with EMT morphological features and chemotherapy resistance [ 106 ]. Independent of platelet activity, EMT has been shown to impart chemotherapy resistance in lung [ 107 ], pancreatic [ 108 ], breast [ 109 ] and ovarian cancers [ 110 ]. Zheng et al, demonstrated using a pancreatic adenocarcinoma mouse model with deleted mesenchymal transcriptional factors, Snail and Twist, that EMT inhibition did not prevent metastasis but contributed significantly to enhanced gemcitabine sensitivity [ 111 ].…”

The crossroads of breast cancer progression: insights into the modulation of major signaling pathways

“…Cross talk between ERα and several EMT regulators, such as Snail and Slug, leads to increased EMT. 362 Additionally, ER signaling can mediate delocalization of E-cadherin and cytoskeleton reorganization via the ER–Src–PELP1–PI3K–ILK1 pathway. Therefore, this cross talk can affect breast cancer progression, leading to metastasis via EMT and contributing to breast cancer cell motility.…”