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Cell Cycle. 2016 Sep;15(17):2265-74. doi: 10.1080/15384101.2016.1160982. Epub 2016 Mar 30.

Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer.

Author information

1
a Radiation Oncology Department , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
2
b Radiation Oncology Branch , National Cancer Institute , Bethesda , MD , USA.
3
c Department of Pathology , Sidney Kimmel Medical College of Thomas Jefferson University , Philadelphia , PA , USA.
4
d Radiation Oncology Department , Miami Cancer Institute , Miami , FL , USA.

Abstract

PURPOSE:

Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease.

METHODS:

An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model.

RESULTS:

CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR.

CONCLUSIONS:

CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer.

KEYWORDS:

Caloric restriction; breast cancer; metastases

PMID:
27027731
PMCID:
PMC5004690
DOI:
10.1080/15384101.2016.1160982
[Indexed for MEDLINE]
Free PMC Article

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