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Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface.

Publication ,  Journal Article
Nelson, ER; Li, S; Kennedy, M; Payne, S; Kilibarda, K; Groth, J; Bowie, M; Parilla-Castellar, E; de Ridder, G; Marcom, PK; Lyes, M; Cook, M ...
Published in: Oncotarget
December 20, 2016

BACKGROUND: Although most triple-negative breast cancer (TNBC) patients initially respond to chemotherapy, residual tumor cells frequently persist and drive recurrent tumor growth. Previous studies from our laboratory and others' indicate that TNBC is heterogeneous, being composed of chemo-sensitive and chemo-resistant tumor cell subpopulations. In the current work, we studied the invasive behaviors of chemo-resistant TNBC, and sought to identify markers of invasion in chemo-residual TNBC. METHODS: The invasive behavior of TNBC tumor cells surviving short-term chemotherapy treatment in vitro was studied using transwell invasion assays and an experimental metastasis model. mRNA expression levels of neural cadherin (N-cadherin), an adhesion molecule that promotes invasion, was assessed by PCR. Expression of N-cadherin and its precursor form (pro-N-cadherin) was assessed by immunoblotting and flow cytometry. Pro-N-cadherin immunohistochemistry was performed on tumors obtained from patients pre- and post- neoadjuvant chemotherapy treatment. RESULTS: TNBC cells surviving short-term chemotherapy treatment exhibited increased invasive behavior and capacity to colonize metastatic sites compared to untreated tumor cells. The invasive behavior of chemo-resistant cells was associated with their increased cell surface expression of precursor N-cadherin (pro-N-cadherin). An antibody specific for the precursor domain of N-cadherin inhibited invasion of chemo-resistant TNBC cells. To begin to validate our findings in humans, we showed that the percent cell surface pro-N-cadherin (+) tumor cells increased in patients post- chemotherapy treatment. CONCLUSIONS: TNBC cells surviving short-term chemotherapy treatment are more invasive than bulk tumor cells. Cell surface pro-N-cadherin expression is associated with the invasive and chemo-resistant behaviors of this tumor cell subset. Our findings indicate the importance of future studies determining the value of cell surface pro-N-cadherin as: 1) a biomarker for TNBC recurrence and 2) a therapeutic target for eliminating chemo-residual disease.

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Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

December 20, 2016

Volume

7

Issue

51

Start / End Page

84030 / 84042

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Burden
  • Triple Negative Breast Neoplasms
  • Time Factors
  • Taxoids
  • Protein Precursors
  • Neoplasm Invasiveness
  • Neoadjuvant Therapy
  • Mice, SCID
  • Mice, Inbred NOD
 

Citation

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Nelson, E. R., Li, S., Kennedy, M., Payne, S., Kilibarda, K., Groth, J., … Bachelder, R. E. (2016). Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface. Oncotarget, 7(51), 84030–84042. https://doi.org/10.18632/oncotarget.12767
Nelson, Erik R., Shenduo Li, Margaret Kennedy, Sturgis Payne, Kelly Kilibarda, Jeffrey Groth, Michelle Bowie, et al. “Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface.Oncotarget 7, no. 51 (December 20, 2016): 84030–42. https://doi.org/10.18632/oncotarget.12767.
Nelson ER, Li S, Kennedy M, Payne S, Kilibarda K, Groth J, et al. Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface. Oncotarget. 2016 Dec 20;7(51):84030–42.
Nelson, Erik R., et al. “Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface.Oncotarget, vol. 7, no. 51, Dec. 2016, pp. 84030–42. Pubmed, doi:10.18632/oncotarget.12767.
Nelson ER, Li S, Kennedy M, Payne S, Kilibarda K, Groth J, Bowie M, Parilla-Castellar E, de Ridder G, Marcom PK, Lyes M, Peterson BL, Cook M, Pizzo SV, McDonnell DP, Bachelder RE. Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface. Oncotarget. 2016 Dec 20;7(51):84030–84042.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

December 20, 2016

Volume

7

Issue

51

Start / End Page

84030 / 84042

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Burden
  • Triple Negative Breast Neoplasms
  • Time Factors
  • Taxoids
  • Protein Precursors
  • Neoplasm Invasiveness
  • Neoadjuvant Therapy
  • Mice, SCID
  • Mice, Inbred NOD