TY - JOUR
T1 - A targeted RNAi screen of the breast cancer genome identifies KIF14 and TLN1 as genes that modulate docetaxel chemosensitivity in triple-negative breast cancer
AU - Singel, Stina Mui
AU - Cornelius, Crystal
AU - Batten, Kimberly
AU - Fasciani, Gail
AU - Wright, Woodring E.
AU - Lum, Lawrence
AU - Shay, Jerry W.
PY - 2013/4/15
Y1 - 2013/4/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-13-0082
DO - 10.1158/1078-0432.CCR-13-0082
M3 - Article
C2 - 23479679
AN - SCOPUS:84877098603
SN - 1078-0432
VL - 19
SP - 2061
EP - 2070
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -