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Clin Cancer Res. 2013 Apr 15;19(8):2061-70. doi: 10.1158/1078-0432.CCR-13-0082. Epub 2013 Mar 11.

A targeted RNAi screen of the breast cancer genome identifies KIF14 and TLN1 as genes that modulate docetaxel chemosensitivity in triple-negative breast cancer.

Author information

1
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Abstract

PURPOSE:

To identify biomarkers within the breast cancer genome that may predict chemosensitivity in breast cancer.

EXPERIMENTAL DESIGN:

We conducted an RNA interference (RNAi) screen within the breast cancer genome for genes whose loss-of-function enhanced docetaxel chemosensitivity in an estrogen receptor-negative, progesterone receptor-negative, and Her2-negative (ER-, PR-, and Her2-, respectively) breast cancer cell line, MDA-MB-231. Top candidates were tested for their ability to modulate chemosensitivity in 8 breast cancer cell lines and to show in vivo chemosensitivity in a mouse xenograft model.

RESULTS:

From ranking chemosensitivity of 328 short hairpin RNA (shRNA) MDA-MB-231 cell lines (targeting 133 genes with known somatic mutations in breast cancer), we focused on the top two genes, kinesin family member 14 (KIF14) and talin 1 (TLN1). KIF14 and TLN1 loss-of-function significantly enhanced chemosensitivity in four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, HCC38, HCC1937, and Hs478T) but not in three hormone receptor-positive cell lines (MCF7, T47D, and HCC1428) or normal human mammary epithelial cells (HMEC). Decreased expression of KIF14, but not TLN1, also enhanced docetaxel sensitivity in a Her2-amplified breast cancer cell line, SUM190PT. Higher KIF14 and TLN1 expressions are found in TNBCs compared with the other clinical subtypes. Mammary fat pad xenografts of KIF14- and TLN1-deficient MDA-MB-231 cells revealed reduced tumor mass compared with control MDA-MB-231 cells after chemotherapy. KIF14 expression is also prognostic of relapse-free and overall survival in representative breast cancer expression arrays.

CONCLUSION:

KIF14 and TLN1 are modulators of response to docetaxel and potential therapeutic targets in TNBC.

PMID:
23479679
PMCID:
PMC4513911
DOI:
10.1158/1078-0432.CCR-13-0082
[Indexed for MEDLINE]
Free PMC Article

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