title: Prognostic and biological significance of proliferation and HER2 expression in the luminal class of breast cancer.
abstract: The definition of Luminal-B subclass of breast cancer (BC) varies in literature. In this study, we have compared the proliferation status; assessed using KI67 labeling index (KI67-LI), and HER2-expression in estrogen receptor positive (ER+) BC to assess their impact on the biological and clinical characteristics of luminal-BC. 1547 (73.8 %) well-characterized clinically annotated stage I-III ER + BC were assessed for expression of KI67, HER2 (ASCO guidelines), and a large panel of relevant biomarkers (no = 37). 46.3 % of the cases show high KI67-LI (>13 %) and 8.4 % show HER2+ and both markers are positively associated with younger age, higher tumor grade and poorer outcome. High KI67-LI and HER2+ are associated with upregulation of ER-coactivators and proliferation-related markers and with downregulation of good prognostic markers. High KI67-LI is associated with larger size, advanced stage, and lymphovascular invasion (LVI) and with downregulation of luminal-enriched and DNA-damage repair markers. In contrast, HER2+ is associated with upregulation of ER-regulated proteins and E-cadherin. When analysis is restricted to high KI67-LI subgroup, HER2+ shows an association with upregulation of differentiation-associated proteins and E-cadherin. Conversely, within HER2+ class, high KI67-LI maintains its association with downregulation of differentiation-associated/luminal-enriched proteins. Outcome analyses indicate that both markers are independently associated with shorter survival but HER2+ is associated with a worse outcome. Although both are associated with high proliferation and poor prognosis within ER + BC, HER2+ is less frequent than high KI67-LI. Unlike KI67, HER2 seems to independently drive the aggressive behavior of ER+ tumors without downregulation of luminal proteins.
authors.affiliation: Department of Histopathology, 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: M
authors.initials: M
authors.lastname: Alabdullah
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.forename: Alaa
authors.initials: A
authors.lastname: Alshareeda
authors.forename: R D
authors.initials: RD
authors.lastname: Macmillan
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human