Premium
In vivo longitudinal imaging of RNA interference‐induced endocrine therapy resistance in breast cancer
Author(s) -
Biswal Nrusingh C.,
Fu Xiaoyong,
Jagtap Jaidip M.,
Shea Martin J.,
Kumar Vijetha,
Lords Tamika,
Roy Ronita,
Schiff Rachel,
Joshi Amit
Publication year - 2020
Publication title -
journal of biophotonics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.877
H-Index - 66
eISSN - 1864-0648
pISSN - 1864-063X
DOI - 10.1002/jbio.201900180
Subject(s) - fulvestrant , tensin , pten , small hairpin rna , cancer research , breast cancer , gene knockdown , estrogen receptor , medicine , cancer , biology , pi3k/akt/mtor pathway , microbiology and biotechnology , signal transduction , cell culture , genetics
Endocrine therapy resistance in breast cancer is a major obstacle in the treatment of patients with estrogen receptor‐positive (ER+) tumors. Herein, we demonstrate the feasibility of longitudinal, noninvasive and semiquantitative in vivo molecular imaging of resistance to three endocrine therapies by using an inducible fluorescence‐labeled short hairpin RNA (shRNA) system in orthotopic mice xenograft tumors. We employed a dual fluorescent doxycycline (Dox)‐regulated lentiviral inducer system to transfect ER+ MCF7L breast cancer cells, with green fluorescent protein (GFP) expression as a marker of transfection and red fluorescent protein (RFP) expression as a surrogate marker of Dox‐induced tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) knockdown. Xenografted MCF7L tumor‐bearing nude mice were randomized to therapies comprising estrogen deprivation, tamoxifen or an ER degrader (fulvestrant) and an estrogen‐treated control group. Longitudinal imaging was performed by a home‐built multispectral imaging system based on a cooled image intensified charge coupled device camera. The GFP signal, which corresponds to number of viable tumor cells, exhibited excellent correlation to caliper‐measured tumor size ( P << .05). RFP expression was substantially higher in mice exhibiting therapy resistance and strongly and significantly ( P < 1e‐7) correlated with the tumor size progression for the mice with shRNA‐induced PTEN knockdown. PTEN loss was strongly correlated with resistance to estrogen deprivation, tamoxifen and fulvestrant therapies.