title: High expression of integrin β6 in association with the Rho-Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers.
abstract: Integrin αvβ6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin β6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvβ6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens (N = 460) for the expression of integrin β6 (ITGB6) mRNA by qPCR. In addition, we have examined a subset (N = 147) for the expression of αvβ6 integrin by immunohistochemistry (IHC). The expression levels of members of Rho-Rac pathway including downstream genes (ACTR2, ACTR3) and effector proteinases (MMP9, MMP15) were estimated by qPCR in the HER2+ subset (N = 59). There is a significant increase in the mean expression of ITGB6 in HER2+ tumors compared to HR+HER2- and triple negative (TNBC) subtypes (P = 0.00). HER2+ tumors with the highest levels (top quartile) of ITGB6 have significantly elevated levels of all the genes of the Rho-Rac pathway (P-values from 0.01 to 0.0001). Patients in this group have a significantly shorter disease-free survival compared to the group with lower ITGB6 levels (HR = 2.9 (0.9-8.9), P = 0.05). The mean level of ITGB6 expression is increased further in lymph node-positive tumors. The increased regional and distant metastasis observed in HER2+ tumors with high levels of ITGB6 might be mediated by the canonical Rho-Rac pathway through increased expression of MMP9 and MMP15.
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Krisha
authors.initials: K
authors.lastname: Desai
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Madhumathy G
authors.initials: MG
authors.lastname: Nair
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Jyothi S
authors.initials: JS
authors.lastname: Prabhu
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Anupama
authors.initials: A
authors.lastname: Vinod
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Aruna
authors.initials: A
authors.lastname: Korlimarla
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Savitha
authors.initials: S
authors.lastname: Rajarajan
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Radhika
authors.initials: R
authors.lastname: Aiyappa
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Rohini S
authors.initials: RS
authors.lastname: Kaluve
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Annie
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: P S
authors.initials: PS
authors.lastname: Hari
authors.affiliation: Kidwai Medical Institute of Oncology, Bangalore, India.
authors.forename: Geetashree
authors.initials: G
authors.lastname: Mukherjee
authors.affiliation: Kidwai Medical Institute of Oncology, Bangalore, India.
authors.forename: Rekha V
authors.initials: RV
authors.lastname: Kumar
authors.affiliation: St. John's Medical College and Hospital, Bangalore, India.
authors.forename: Suraj
authors.initials: S
authors.lastname: Manjunath
authors.affiliation: St. John's Medical College and Hospital, Bangalore, India.
authors.forename: Marjorrie
authors.initials: M
authors.lastname: Correa
authors.affiliation: Shankara Cancer Hospital and Research Centre, Bangalore, India.
authors.forename: B S
authors.initials: BS
authors.lastname: Srinath
authors.affiliation: Shankara Cancer Hospital and Research Centre, Bangalore, India.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Patil
authors.affiliation: Shankara Cancer Hospital and Research Centre, Bangalore, India.
authors.forename: M S N
authors.initials: MS
authors.lastname: Prasad
authors.affiliation: Rangadore Memorial Hospital, Bangalore, India.
authors.forename: K S
authors.initials: KS
authors.lastname: Gopinath
authors.affiliation: Rangadore Memorial Hospital, Bangalore, India.
authors.forename: Raman N
authors.initials: RN
authors.lastname: Rao
authors.affiliation: Biogen Inc., Cambridge, MA.
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.affiliation: Biogen Inc., Cambridge, MA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: T S
authors.initials: TS
authors.lastname: Sridhar
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D039641:Integrin beta Chains / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D039641:Integrin beta Chains; D018719:Erb-b2 Receptor Tyrosine Kinases; D020744:rac GTP-Binding Proteins; C072170:integrin beta6
keywords: Breast cancer; HER2 subtype; MMP; Rho-Rac; integrin αvβ6; invasion