title: Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy.
abstract: BACKGROUND
  Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44(>)/CD24(>/low)) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44(>) and CD24(>/low) cell population.
  
  
  METHODS
  Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided.
  
  
  RESULTS
  Chemotherapy treatment increased the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P < .001) and increased mammosphere formation efficiency (MSFE) (mean at baseline vs 12 weeks, 13.3%, 95% CI = 6.0% to 20.6%, vs 53.2%, 95% CI = 42.4% to 64.0%; P < .001). Conversely, lapatinib treatment of patients with HER2-positive tumors led to a non-statistically significant decrease in the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a statistically non-significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%).
  
  
  CONCLUSIONS
  These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.
authors.affiliation: Breast Center at Baylor College of Medicine, 1 Baylor Plaza BCM 600, TX 77030, USA.
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Li
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Carolina
authors.initials: C
authors.lastname: Gutierrez
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: Anne
authors.initials: A
authors.lastname: Pavlick
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.forename: Gary C
authors.initials: GC
authors.lastname: Chamness
authors.forename: Helen
authors.initials: H
authors.lastname: Wong
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rosen
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012107:Research Design
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone