The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer

Rabia A. Gilani, Armina A. Kazi, Preeti Shah, Amanda J. Schech, Saranya Chumsri, Gauri Sabnis, Anil K. Jaiswal, Angela H. Brodie

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Aromatase inhibitors (AIs) are an effective therapy in treating estrogen receptor-positive breast cancer. Nonetheless, a significant percentage of patients either do not respond or become resistant to AIs. Decreased dependence on ER-signaling and increased dependence on growth factor receptor signaling pathways, particularly human epidermal growth factor receptor 2 (EGFR2/ HER2), have been implicated in AI resistance. However, the role of growth factor signaling remains unclear. This current study investigates the possibility that signaling either through HER2 alone or through interplay between epidermal growth factor receptor 1 (EGFR/HER1) and HER2 mediates AI resistance by increasing the tumor initiating cell (TIC) subpopulation in AI-resistant cells via regulation of stem cell markers, such as breast cancer resistance protein (BCRP). TICs and BCRP are both known to be involved in drug resistance. Results from in vitro analyses of AI-resistant versus AI-sensitive cells and HER2-versus HER2+ cells, as well as from in vivo xenograft tumors, indicate that (1) AI-resistant cells overexpress both HER2 and BCRP and exhibit increased TIC characteristics compared to AI-sensitive cells; (2) inhibition of HER2 and/or BCRP decrease TIC characteristics in letrozole-resistant cells; and (3) HER2 and its dimerization partner EGFR/HER1 are involved in the regulation of BCRP. Overall, these results suggest that reducing or eliminating the TIC subpopulation with agents that target BCRP, HER2, EGFR/HER1, and/or their downstream kinase pathways could be effective in preventing and/or treating acquired AI resistance.

Original languageEnglish (US)
Pages (from-to)681-692
Number of pages12
JournalBreast Cancer Research and Treatment
Volume135
Issue number3
DOIs
StatePublished - Oct 2012
Externally publishedYes

Fingerprint

Aromatase Inhibitors
Neoplastic Stem Cells
Breast Neoplasms
Population
Proteins
letrozole
Growth Factor Receptors
Dimerization
Epidermal Growth Factor Receptor
Drug Resistance
Heterografts
Estrogen Receptors
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Stem Cells

Keywords

  • Aromatase inhibitor
  • BCRP
  • Breast cancer
  • HER2
  • Hormone or endocrine therapy
  • Lapatinib
  • Tumor initiating cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer. / Gilani, Rabia A.; Kazi, Armina A.; Shah, Preeti; Schech, Amanda J.; Chumsri, Saranya; Sabnis, Gauri; Jaiswal, Anil K.; Brodie, Angela H.

In: Breast Cancer Research and Treatment, Vol. 135, No. 3, 10.2012, p. 681-692.

Research output: Contribution to journalArticle

Gilani, Rabia A. ; Kazi, Armina A. ; Shah, Preeti ; Schech, Amanda J. ; Chumsri, Saranya ; Sabnis, Gauri ; Jaiswal, Anil K. ; Brodie, Angela H. / The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer. In: Breast Cancer Research and Treatment. 2012 ; Vol. 135, No. 3. pp. 681-692.
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