A mutual activation loop between the Ca2+-activated chloride channel TMEM16A and EGFR/STAT3 signaling promotes breast cancer tumorigenesis.

Abstract

The Ca2+-activated chloride channel TMEM16A (anoctamin 1) is overexpressed in breast cancer. It remains unclear how TMEM16A overexpression plays a role in carcinogenesis in breast cancer. In this study, we found that high TMEM16A expression in combination with high EGFR or STAT3 expression was significantly associated with shorter overall survival in ER-positive breast cancer patients without tamoxifen treatment, and longer overall survival in patients with tamoxifen treatment. EGFR/STAT3 signaling activation by EGF promoted TMEM16A expression, and TMEM16A overexpression activated EGFR/STAT3 signaling in breast cancer cells. Both in vitro and in animal studies showed that TMEM16A overexpression promoted, and TMEM16A knockdown inhibited breast cancer cell proliferation and tumor growth. In addition, TMEM16A overexpression-induced cell proliferation was blocked by EGFR/STAT3 inhibitors, and TMEM16A knockdown reduced EGF-induced proliferation and tumorigenesis in breast cancer. Furthermore, inhibition of TMEM16A channel function effectively reduced breast cancer cell proliferation, especially in combination with EGFR inhibitors. Our findings identify a mutual activation loop between TMEM16A and EGFR/STAT3 signaling, which is important for breast cancer proliferation and growth. TMEM16A inhibition may represent a novel therapy for EGFR-expressing breast cancer.

• Authors: Hui Wang, Fan Yao, Shuya Luo, Ke Ma, Mei Liu, Lichuan Bai, Si Chen, Chang Song, Tianyu Wang, Qiang Du, Huizhe Wu, Minjie Wei, Yue Fang, Qinghuan Xiao
• Journal: Cancer letters (Cancer Lett) Vol. 455 Pg. 48-59 (07 28 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 31042586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• ANO1 protein, human
• Anoctamin-1
• Neoplasm Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• EGFR protein, human
• ErbB Receptors

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Anoctamin-1 (biosynthesis, metabolism)
• Breast Neoplasms (metabolism, pathology)
• Carcinogenesis
• Cell Line, Tumor
• ErbB Receptors (biosynthesis, metabolism)
• Female
• Heterografts
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Neoplasm Proteins (biosynthesis, metabolism)
• STAT3 Transcription Factor (biosynthesis, metabolism)
• Signal Transduction
• Young Adult