title: The mammalian target of rapamycin complex 1 (mTORC1) in breast cancer: the impact of oestrogen receptor and HER2 pathways.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) is a downstream of the PI3K/Akt pathway which affects cancer development. mTORC1 has many downstream signalling effectors that can enhance different cellular responses. This study aims to investigate the expression of mTORC1 in breast cancer (BC) and correlate it with key clinicopathological and molecular features of BC especially to proteins related to oestrogen receptor (ER) and HER2 pathways in different BC classes. Moreover, mTORC1 expression was assessed in 6 BC cell lines including ER+ and ER- cell lines with and without HER2 transfection. Immunohistochemistry was used to assess the expression of phospho (p) mTORC1 in a large (n = 1300) annotated BC series prepared as tissue microarray. Reverse phase protein array (RPPA) was used to assess its expression in the different BC cell lines. The expression of p-mTORC1 was cytoplasmic with moderate/high expression noted in 44 % of BC. p-mTORC1 expression was associated with clinicopathological variables characteristic of good prognosis. Positive correlation with ER, ER-related proteins AKT, PI3K and luminal differentiation markers were observed in the whole series and in the ER+HER2- subgroup. Association with HER2 was mainly observed in the ER-negative class. RPPA indicated that p-mTORC1 expression was mainly related to ER expression and with better outcome in the Akt positive tumours. p-mTORC1 is associated with good prognostic features. Its expression is related to ER and ER related proteins in addition to AKT and PI3K. Its relation with HER2 expression is mainly seen in the absence of ER expression.
authors.affiliation: Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, Nottingham City Hospital, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK, denaakramj@yahoo.co.uk.
authors.forename: Dena A
authors.initials: DA
authors.lastname: Jerjees
authors.forename: Ola H
authors.initials: OH
authors.lastname: Negm
authors.forename: M Layth
authors.initials: ML
authors.lastname: Alabdullah
authors.forename: Sameer
authors.initials: S
authors.lastname: Mirza
authors.forename: Methaq
authors.initials: M
authors.lastname: Alkaabi
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Hameed
authors.forename: Rezvan
authors.initials: R
authors.lastname: Abduljabbar
authors.forename: Abir
authors.initials: A
authors.lastname: Muftah
authors.forename: Chris C
authors.initials: CC
authors.lastname: Nolan
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Tighe
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism*; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D058570:TOR Serine-Threonine Kinases