title: Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface.
abstract: 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.
authors: Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors: Erik R
authors: ER
authors: Nelson
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Shenduo
authors: S
authors: Li
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Margaret
authors: M
authors: Kennedy
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Sturgis
authors: S
authors: Payne
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Kelly
authors: K
authors: Kilibarda
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Jeffrey
authors: J
authors: Groth
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Michelle
authors: M
authors: Bowie
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Edgardo
authors: E
authors: Parilla-Castellar
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Gustaaf
authors: G
authors: de Ridder
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Paul Kelly
authors: PK
authors: Marcom
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Matthew
authors: M
authors: Lyes
authors: Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
authors: Bercedis L
authors: BL
authors: Peterson
authors: Department of Immunology, Duke University School of Medicine, Durham, NC, USA.
authors: Michael
authors: M
authors: Cook
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Salvatore V
authors: SV
authors: Pizzo
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors: Donald P
authors: DP
authors: McDonnell
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: Robin E
authors: RE
authors: Bachelder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D017024:Chemotherapy, Adjuvant; D000077143:Docetaxel; D005260:Female; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015820:Cadherins; C489083:Cdh2 protein, mouse; D011498:Protein Precursors; D043823:Taxoids; D000077143:Docetaxel
keywords: Precursor-N-cadherin; chemotherapy resistance; invasion; metastasis; triple-negative breast cancer