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

Li,Youqiang; Wu,Yanyuan; Abbatiello,Thomas C.; Wu,Warren L.; Kim,Ju Ri; Sarkissyan,Marianna; Sarkissyan,Suren; Chung,Seyung S.; Elshimali,Yahya; Vadgama,Jaydutt V.

doi:10.3892/ijo.2015.2878

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

Authors:
- Youqiang Li
- Yanyuan Wu
- Thomas C. Abbatiello
- Warren L. Wu
- Ju Ri Kim
- Marianna Sarkissyan
- Suren Sarkissyan
- Seyung S. Chung
- Yahya Elshimali
- Jaydutt V. Vadgama
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Affiliations: Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
Published online on: February 5, 2015 https://doi.org/10.3892/ijo.2015.2878
Pages: 1461-1472
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.

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