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Targeting interferon response genes sensitizes aromatase inhibitor resistant breast cancer cells to estrogen-induced cell death


Research article

Hye Joung Choi1, Asona Lui12, Joshua Ogony1, Rifat Jan3, Peter J Sims4 and Joan Lewis-Wambi12*

  • *
    Corresponding author: Joan Lewis-Wambi jlewis-wambi@kumc.edu

Author Affiliations

1 Department of Cancer Biology, University of Kansas Medical Center, Kansas City 66160, KS, USA

2 Department of Physiology, University of Kansas Medical Center, Kansas City 66160, KS, USA

3 Cancer Biology Program, Research Institute of Fox Chase Cancer Center, Philadelphia 19111, PA, USA

4 Department of Pathology and Laboratory Medicine, University of Rochester, Rochester 14642, NY, USA

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Breast Cancer Research 2015, 17:6 

Published: 15 January 2015

Abstract (provisional)

IntroductionEstrogen deprivation using aromatase inhibitors (AIs) is currently the
standard of care for postmenopausal women with hormone receptor-positive breast cancer.
Unfortunately, the majority of patients treated with AIs eventually develop resistance,
inevitably resulting in patient relapse and, ultimately, death. The mechanism by which
resistance occurs is still not completely known, however, recent studies suggest that
impaired/defective interferon signaling might play a role. In the present study, we
assessed the functional role of IFITM1 and PLSCR1; two well-known interferon response
genes in AI resistance.MethodsReal-time PCR and Western blot analyses were used to
assess mRNA and protein levels of IFITM1, PLSCR1, STAT1, STAT2, and IRF-7 in AI-resistant
MCF-7:5C breast cancer cells and AI-sensitive MCF-7 and T47D cells. Immunohistochemistry
(IHC) staining was performed on tissue microarrays consisting of normal breast tissues,
primary breast tumors, and AI-resistant recurrence tumors. Enzyme-linked immunosorbent
assay was used to quantitate intracellular IFN? level. Neutralizing antibody was used
to block type 1 interferon receptor IFNAR1 signaling. Small interference RNA (siRNA)
was used to knockdown IFITM1, PLSCR1, STAT1, STAT2, IRF-7, and IFN? expression.ResultsWe
found that IFITM1 and PLSCR1 were constitutively overexpressed in AI-resistant MCF-7:5C
breast cancer cells and AI-resistant tumors and that siRNA knockdown of IFITM1 significantly
inhibited the ability of the resistant cells to proliferate, migrate, and invade.
Interestingly, suppression of IFITM1 significantly enhanced estradiol-induced cell
death in AI-resistant MCF-7:5C cells and markedly increased expression of p21, Bax,
and Noxa in these cells. Significantly elevated level of IFN? was detected in AI-resistant
MCF-7:5C cells compared to parental MCF-7 cells and suppression of IFN? dramatically
reduced IFITM1 PLSCR1, p-STAT1, and p-STAT2 expression in the resistant cells. Lastly,
neutralizing antibody against IFNAR1/2 and knockdown of STAT1/STAT2 completely suppressed
IFITM1, PLSCR1, p-STAT1, and p-STAT2 expression in the resistant cells, thus confirming
the involvement of the canonical IFN? signaling pathway in driving the overexpression
of IFITM1 and other interferon-stimulated genes (ISGs) in the resistant cells.ConclusionOverall,
these results demonstrate that constitutive overexpression of ISGs enhances the progression
of AI-resistant breast cancer and that suppression of IFITM1 and other ISGs sensitizes
AI-resistant cells to estrogen-induced cell death.