Heterogeneity within molecular subtypes of breast cancer

Abstract

Breast cancer is the quintessential example of how molecular characterization of tumor biology guides therapeutic decisions. From the discovery of the estrogen receptor to current clinical molecular profiles to evolving single-cell analytics, the characterization and compartmentalization of breast cancer into divergent subtypes is clear. However, competing with this divergent model of breast cancer is the recognition of intratumoral heterogeneity, which acknowledges the possibility that multiple different subtypes exist within a single tumor. Intratumoral heterogeneity is driven by both intrinsic effects of the tumor cells themselves as well as extrinsic effects from the surrounding microenvironment. There is emerging evidence that these intratumoral molecular subtypes are not static; rather, plasticity between divergent subtypes is possible. Interconversion between seemingly different subtypes within a tumor drives tumor progression, metastases, and treatment resistance. Therapeutic strategies must, therefore, contend with changing phenotypes in an individual patient's tumor. Identifying targetable drivers of molecular heterogeneity may improve treatment durability and disease progression.

Keywords: cell-state heterogeneity; dynamic interconversion; hierarchical heterogeneity; intratumoral heterogeneity; plasticity.

Figure 1.

Molecular classification schema for breast cancer. A proposed model for understanding how molecular subtypes correspond to the initial molecular schema of ER⁺/PR⁺, HER2⁺, and TNBC. The PAM50 gene signature organizes breast cancers into five distinct subtypes: luminal A, luminal B, normal-like, basal, and HER2-enriched, with further classification of the distinct claudin-low subtype (2, 20). At the same time, the TNBC subtype was defined into four distinct subtypes: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), and luminal androgen receptor (LAR) (25). ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PAM50, prediction analysis of microarray 50; PR, progesterone receptor; TNBC, triple negative breast cancer.

Figure 2.

Causes and consequences of molecular heterogeneity. Listed above are potential drivers of multiple different breast cancer subtypes in a single tumor and resulting effects. The formation of intratumoral heterogeneity can be caused by multiple different breast cancer stem cells, dynamic conversion between subtypes, cell-state transitions, and tumor microenvironmental factors, among other factors. Repercussions of these phenomena are the development of metastatic disease and a treatment-resistant phenotype. Created with BioRender.com. ADLH, aldehyde dehydrogenase; CD, cluster of differentiation; HER2, human epidermal growth factor receptor 2; PROCR, protein C receptor; TNBC, triple negative breast cancer.

Figure 3.

Proposed cell-state heterogeneity among PAM50 subtypes. Within a single breast tumor, where at the bulk level, the tumor is classified according to the dominant subpopulation into the appropriate PAM50 subtype (HER2-enriched, basal-like, normal-like, luminal A, and luminal B), there can exist cell-state diversity masked at the bulk level. Herein, we show a fluid model of tumor cell states corresponding to the cell states in the development of normal mammary tissue. Within each tumor subtype there can exist a plurality of cell states, with implications including the need to account for cell-state heterogeneity. The presence of multiple cell states would correspond to multiple potential therapeutic targets accounting for each cell state. HER2, human epidermal growth factor receptor 2; PAM50, prediction analysis of microarray 50.