Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR

Abstract

Triple-negative breast cancer (TNBC) does not express conventional therapeutic targets and is the only type of malignant breast cancer for which no designated FDA-approved targeted therapy is available. Although overexpression of epidermal growth factor receptor (EGFR) is frequently found in TNBC, the therapeutic effect of EGFR inhibitors in TNBC has been underwhelming. Here we show that co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) results in synergistic growth inhibition in TNBC cells. The dual treatment leads to synergistic repression of the long non-coding RNA (lncRNA) HOTAIR (HOX Antisense Intergenic RNA). HOTAIR has been known to induce tumor growth and metastasis in breast cancer. Depleting HOTAIR alone phenocopies the dual treatment in growth suppression. We show that expression of HOTAIR is regulated by β-catenin through a LEF1/TCF4-binding site. The dual treatment blocks nuclear expression of β-catenin and prevents its recruitment to the HOTAIR promoter. Consistently, forced expression of β-catenin rescued HOTAIR expression and cell viability in the presence of both drugs. Upregulation of HOTAIR is associated with TNBC in cell lines and a cohort of primary tumors. This study elucidates a previously unidentified mechanism in TNBC linking signaling with lncRNA regulation which may be exploited for therapeutic gain.

Long Non-Coding RNA XLOC_008466 Functions as an Oncogene in Human Non-Small Cell Lung Cancer by Targeting miR-874

“…HOTAIR has been extensively studied in cancer [22]. Its expression has been shown to regulate breast and lung cancer cell growth and metastasis [23, 24]. In our study, up-regulation of XLOC_008466 was confirmed in NSCLC tissues and is associated with lymph node metastasis and the TNM stage.…”

Multifunctional Abl kinases in health and disease

“…In estrogen receptor (ER)-positive breast cancer cells, ABL is a functional partner of ERs, and inhibition of ABL resulted in sensitization to anti-estrogen therapies with tamoxifen, fulvestrant and aromatase inhibitors (Esparza-Lopez et al, 2013;Weigel et al, 2013;Zhao et al, 2011Zhao et al, , 2010. In addition, inhibition of ABL1 has been reported to sensitize breast cancer cells to the EGFR and ERBB receptor tyrosine kinase inhibitor lapatinib Stuhlmiller et al, 2015;Wang et al, 2015), and prostate and renal cancer cells to inhibitors of heat shock protein 90 (Hsp90) (Dunn et al, 2015) (see poster).…”

Noncoding RNAs in breast cancer

“…This facilitates the ligand-independent activation of ER, which contributes to tamoxifen resistance [179]. Moreover, upregulation of HOTAIR was also found in triple-negative breast cancer (TNBC) cell lines in addition to primary breast tumors [180]. Suppression of HOTAIR expression by co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) resulted in synergistic growth inhibition in TNBC cells [180].…”

“…Moreover, upregulation of HOTAIR was also found in triple-negative breast cancer (TNBC) cell lines in addition to primary breast tumors [180]. Suppression of HOTAIR expression by co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) resulted in synergistic growth inhibition in TNBC cells [180]. This dual treatment effect was mediated by blocking nuclear expression of b-catenin and preventing its recruitment to the HOTAIR promoter [180].…”

“…Suppression of HOTAIR expression by co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) resulted in synergistic growth inhibition in TNBC cells [180]. This dual treatment effect was mediated by blocking nuclear expression of b-catenin and preventing its recruitment to the HOTAIR promoter [180]. A recent report has also shown that HOTAIR is involved in triggering EMT in breast cancer cells and maintaining BCSCs [181].…”