HER2-Positive Breast Cancer Pathophysiology



Human epidermal growth factor receptor 2 (HER2) is a ligand orphan receptor tyrosine kinase that forms heterodimers with other members of the HER family (HER-1, HER-3, and HER-4), amplifying their signal.1 HER-2 is an activator of several downstream signaling cascades, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI3K) pathways; diversity of downstream signaling can occur through variations in the activating ligand and the composition of the HER-2 dimer.1 Activation of HER-2 causes alterations in gene expression mediated through changes in transcription, translation, and protein stability, which affect cell growth, proliferation, migration, adhesion, and survival.1

These tumors are often negative for estrogen (ER) and progesterone (PR) hormone receptors, and comprise the subtype “HER2-enriched”.2,3 HR-/HER2+ cancers previously had the worst prognosis; however, outcomes have substantially improved with HER2-targeted therapy.3 Tumors with hormone receptor positivity (HR+) comprise the subtype “Luminal B” and tend to be of higher grade than some of the other breast cancer subtypes.3  HR+/HER2+ tumors can be defined by high positivity for the protein Ki67, an indicator of a large number of actively dividing cells, and/or HER2.3


Overexpression of HER2 is found in 20% to 30% of breast cancers. These tumors are particularly aggressive, have a higher recurrence rate and cause increased mortality.1,4


The HER2 gene is located on long arm of chromosome 17 and encodes a 185-kDa transmembrane protein.4 HER-2 has an extracellular ligand–binding domain, a transmembrane domain, and an intracellular tyrosine kinase catalytic domain. On ligand activation, the receptors dimerize forming heterodimers.5

Prognostic Significance

Controversy surrounds the value of HER2 as a prognostic factor, as abnormalities in HER2 expression at the gene or protein level have been associated with an adverse prognosis in both lymph node–negative and lymph node–positive breast cancer in many cases.6


  1. Advances in Targeting Human Epidermal Growth Factor Receptor-2 Signaling for Cancer Therapy (Funda Meric-Bernstam and Mien-Chie Hung) https://clincancerres.aacrjournals.org/content/12/21/6326
  2. Joe BN. Clinical features, diagnosis, and staging of newly diagnosed breast cancer. 2020 UpToDate; Wolters Kluwer. https://www.uptodate.com/contents/clinical-features-diagnosis-and-staging-of-newly-diagnosed-breast-cancer?search=ER%2FPR%20HER2%2B%20breast%20cancer&source=search_result&selectedTitle=5~150&usage_type=default&display_rank=5.  Accessed July 2020.
  3. American Cancer Society. Breast Cancer Facts and Figures 2019-2020. Available: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf. Accessed July 2020.
  4. The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy (Zahi Mitri, Tina Constantine, and Ruth O’Regan ) https://www.hindawi.com/journals/cherp/2012/743193/
  5. HER2 in Breast Cancer: A Review and Update (Krishnamurti, Uma MD, PhD; Silverman, Jan F. MD) https://journals.lww.com/anatomicpathology/Fulltext/2014/03000/HER2_in_Breast_Cancer___A_Review_and_Update.4.aspx
  6. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14: 320–368. https://theoncologist.onlinelibrary.wiley.com/doi/full/10.1634/theoncologist.2008-0230