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

Brittany A. Simone, Tu Dan, Ajay Palagani, Lianjin Jin, Sunny Y. Han, Christopher Wright, Jason E. Savage, Robert Gitman, Meng Kieng Lim, Juan Palazzo, Minesh P. Mehta, Nicole L. Simone

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2265-2274
Number of pages10
JournalCell Cycle
Volume15
Issue number17
DOIs
StatePublished - Sep 1 2016

Fingerprint

Triple Negative Breast Neoplasms
Caloric Restriction
Radiation
Neoplasm Metastasis
Neoplasms
Down-Regulation
Breast Neoplasms
Luciferases
Disease-Free Survival
Radiotherapy
Apoptosis
Cell Line

Keywords

  • breast cancer
  • Caloric restriction
  • metastases

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer. / Simone, Brittany A.; Dan, Tu; Palagani, Ajay; Jin, Lianjin; Han, Sunny Y.; Wright, Christopher; Savage, Jason E.; Gitman, Robert; Lim, Meng Kieng; Palazzo, Juan; Mehta, Minesh P.; Simone, Nicole L.

In: Cell Cycle, Vol. 15, No. 17, 01.09.2016, p. 2265-2274.

Research output: Contribution to journalArticle

Simone, BA, Dan, T, Palagani, A, Jin, L, Han, SY, Wright, C, Savage, JE, Gitman, R, Lim, MK, Palazzo, J, Mehta, MP & Simone, NL 2016, 'Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer', Cell Cycle, vol. 15, no. 17, pp. 2265-2274. https://doi.org/10.1080/15384101.2016.1160982
Simone, Brittany A. ; Dan, Tu ; Palagani, Ajay ; Jin, Lianjin ; Han, Sunny Y. ; Wright, Christopher ; Savage, Jason E. ; Gitman, Robert ; Lim, Meng Kieng ; Palazzo, Juan ; Mehta, Minesh P. ; Simone, Nicole L. / Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer. In: Cell Cycle. 2016 ; Vol. 15, No. 17. pp. 2265-2274.
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AU - Dan, Tu

AU - Palagani, Ajay

AU - Jin, Lianjin

AU - Han, Sunny Y.

AU - Wright, Christopher

AU - Savage, Jason E.

AU - Gitman, Robert

AU - Lim, Meng Kieng

AU - Palazzo, Juan

AU - Mehta, Minesh P.

AU - Simone, Nicole L.

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N2 - 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.

AB - 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.

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