title: HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells.
abstract: Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor-stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF-7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin β6) versus those with low levels. Within the epithelial-to-mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin β6 and growth factor receptors-human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan-Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin β6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin αvβ6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin β6 could mediate epithelial-to-mesenchymal transition and migration in a subset of luminal breast cancers and lapatinib might be effective in disrupting this interaction.
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Krisha
authors.initials: K
authors.lastname: Desai
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Radhika
authors.initials: R
authors.lastname: Aiyappa
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Jyothi S
authors.initials: JS
authors.lastname: Prabhu
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Madhumathy G
authors.initials: MG
authors.lastname: Nair
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Patrick Varun
authors.initials: PV
authors.lastname: Lawrence
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Aruna
authors.initials: A
authors.lastname: Korlimarla
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Anupama
authors.initials: A
authors.lastname: Ce
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Annie
authors.initials: A
authors.lastname: Alexander
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: Rohini S
authors.initials: RS
authors.lastname: Kaluve
authors.affiliation: 2 St. John's Medical College Hospital, Bangalore, India.
authors.forename: Suraj
authors.initials: S
authors.lastname: Manjunath
authors.affiliation: 2 St. John's Medical College Hospital, Bangalore, India.
authors.forename: Marjorrie
authors.initials: M
authors.lastname: Correa
authors.affiliation: 3 Sri Shankara Cancer Hospital and Research Centre, Bangalore, India.
authors.forename: B S
authors.initials: BS
authors.lastname: Srinath
authors.affiliation: 3 Sri Shankara Cancer Hospital and Research Centre, Bangalore, India.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Patil
authors.affiliation: 3 Sri Shankara Cancer Hospital and Research Centre, Bangalore, India.
authors.forename: Anjali
authors.initials: A
authors.lastname: Kalamdani
authors.affiliation: 3 Sri Shankara Cancer Hospital and Research Centre, Bangalore, India.
authors.forename: Msn
authors.initials: M
authors.lastname: Prasad
authors.affiliation: 1 Division of Molecular Medicine, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
authors.forename: T S
authors.initials: TS
authors.lastname: Sridhar
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000096:biosynthesis* / Q000235:genetics; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000071250:Snail Family Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015820:Cadherins; D016023:Integrins; D000077341:Lapatinib; D020780:Matrix Metalloproteinase 9; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000071250:Snail Family Transcription Factors; D053773:Transforming Growth Factor beta1; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; C508960:TGFB1 protein, human; C073878:integrin alphavbeta6; C508053:ERBB2 protein, human; C579270:MMP9 protein, human
keywords: Breast cancer; epithelial-to-mesenchymal transition; growth factor receptors; integrin β6; lapatinib; metastasis