HER2-Negative Breast Cancer Pathophysiology


Human epidermal growth factor receptor 2 (HER2)-negative breast cancers are divided into two categories, also known as subtypes, differentiated by hormone receptor (HR) positivity and negativity.1 HR-positive tumor cells have receptors for estrogen or progesterone, hormones which can promote tumor cell growth.1

Normal Breast Development

  • Estrogens are considered to play a significant role in promoting breast epithelium proliferation.
    • Estradiol stimulates DNA synthesis and promotes bud formation by acting on the mammary gland locally. 2
    • DNA synthesis and bud formation are thought to be predominantly mediated by ER alpha, a nuclear estrogen receptor which activates transcription of specific genes containing the estrogen response elements.3
    • ER-alpha-null knockout mice have been demonstrated to have poorly developed mammary glands, demonstrating the importance of ER-alpha.4
  • Both estrogen and progesterone are required for normal ductal development.5
    • Progesterone, in conjunction with estrogen, regulates breast development through its specific receptor (PR) on breast epithelial cells.5
    • During the normal menstrual cycle, breast epithelium exhibits maximal proliferation during the luteal phase, when progesterone levels are at their highest and estrogen levels have begun to decline.5

Pathophysiology of Hormone Receptor Positive HR+/HER2- Cancer

  • The molecular mechanisms underlying the development of breast cancer, especially estrogen-associated carcinogenesis, are incompletely understood.5
  • Breast carcinogenesis likely results from uncontrolled cellular proliferation and/or abnormal apoptosis, stemming from cumulative genetic injuries that activate proto-oncogenes and/or inactivate tumor suppressor genes.5
    • These genetic alterations can be either:
      • Inherited as germline mutations
      • Acquired (somatic mutations) resulting from cumulative exposure to environmental carcinogens.5
    • The classic two-stage carcinogenesis model of tumor development theorizes that the initiated cells’ genotype alteration is irreversible, and that tumor progression depends upon further, potentially reversible epigenetic changes.5
  • Prolonged exposure to both estrogens and progestins can promote initial tumor formation and early tumor growth, as noted in rodent models of carcinogen-induced and spontaneous mammary cancer.5
  • In vitro studies of cultured human breast epithelial cells, 17-beta estradiol has also been shown to induce phenotypic changes indicative of neoplastic transformation, similar to those induced by the chemical carcinogen benzapyrene.6
  • A clear link between exogenous hormone exposure and breast cancer risk has been demonstrated in human studies.5

Pathophysiology of Hormone Receptor Negative HR-/HER2- Cancer

  • These tumors are in essence called triple negative breast cancers (TNBC), since estrogen and progesterone receptors, as well as HER2 are not expressed.1,7
  • TNBC is characteristically high grade, with infiltrating ductal carcinoma as the most common histology.6
    • A rare histologic subtype, medullary carcinoma, is generally triple negative.6
    • Metaplastic carcinomas, an uncommon subgroup of TNBC, is comprised of a diverse group of cancers ranging from squamous to stromal in nature.6
    • Pathologic features of TNBCs can include geographic necrosis, a pushing border of invasion, and a stromal lymphocytic response.6
  • Although the triple-negative clinical phenotype mostly comprises the basal-like molecular subtype, triple-negative and basal breast cancers are not synonymous, having substantial heterogeneity within TNBCs.7
    • Basal breast cancer is characterized by the genomic expression of the “basal cluster”, a unique cluster of genes that includes: 8,9,10,11
      • Epidermal growth factor receptor (EGFR, also called HER1)
      • Basal cytokeratins 5/6
      • c-Kit
      • Low expression of the hormone receptor- and HER2-related genes.
    • Additional characterized subtypes include claudin-low and interferon-rich.12,13
  • Gene expression analysis of TNBC has also revealed that there is either mutation or aberrant expression of tumor suppressor gene p53 (TP53) and several DNA repair genes, particularly the breast cancer susceptibility genes (BRCA), which may harbor implications for chemotherapeutic sensitivity to platinum and other DNA-damaging agents.14,15


  1. National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Female Breast Cancer Subtypes. Available: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed July 2020.
  2. Role of hormones in mammary cancer initiation and progression. Russo IH, Russo J. J Mammary Gland Biol Neoplasia. 1998;3(1):49.
  3. Effects of steroid hormones and related compounds on gene transcription. King RJ. Clin Endocrinol (Oxf). 1992;36(1):1.
  4. CouseJF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us?. Endocr Rev. 1999;20(3):358.
  5. Russo J. Breast development and morphology. 2020 UpToDate; Wolters Kluwer. https://www.uptodate.com/contents/breast-development-and-morphology. Accessed July 2020.
  6. Russo J, Lareef MH, Tahin Q, et al. 17Beta-estradiol is carcinogenic in human breast epithelial cells.. J Steroid Biochem Mol Biol. 2002;80(2):149.
  7. Anders CK, Carey LA. ER/PR negative, HER2-negative (triple negative) breast cancer. 2020 UpToDate; Wolters Kluwer. https://www.uptodate.com/contents/er-pr-negative-her2-negative-triple-negative-breast-cancer?sectionName=Molecular%20classification%20of%20TNBC&search=human%20epithelial%20growth%20factor%20receptor%202%20breast%20cancer&topicRef=744&anchor=H493962740&source=see_link#H493962740. Accessed July 2020.
  8. Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma.. Mod Pathol. 2006;19(2):264.
  9. Carey LA, Rugo HS, Marcom PK, et al TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer.. J Clin Oncol. 2008;26S:ASCO #1009.
  10. Korsching E, Packeisen J, Agelopoulos K, et al. Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis.. Lab Invest. 2002;82(11):1525.
  11. Nielsen TO, Hsu FD, Jensen K, et al..Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367.
  12. Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol. 2007;8(8):R157.
  13. Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Prat A, Parker JS,. Breast Cancer Res. 2010;12(5):R68. Epub 2010 Sep 2.
  14. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869.
  15. Troester MA, Herschkowitz JI, Oh DS, et al. Gene expression patterns associated with p53 status in breast cancer. BMC Cancer. 2006;6:276. Epub 2006 Dec 6.