The complex nature of heterogeneity and its roles in breast cancer biology and therapeutic responsiveness

Abstract

Heterogeneity is a complex feature of cells and tissues with many interacting components. Depending on the nature of the research context, interacting features of cellular, drug response, genetic, molecular, spatial, temporal, and vascular heterogeneity may be present. We describe the various forms of heterogeneity with examples of their interactions and how they play a role in affecting cellular phenotype and drug responses in breast cancer. While cellular heterogeneity may be the most widely described and invoked, many forms of heterogeneity are evident within the tumor microenvironment and affect responses to the endocrine and cytotoxic drugs widely used in standard clinical care. Drug response heterogeneity is a critical determinant of clinical response and curative potential and also is multifaceted when encountered. The interactive nature of some forms of heterogeneity is readily apparent. For example, the process of metastasis has the properties of both temporal and spatial heterogeneity within the host, whereas each individual metastatic deposit may exhibit cellular, genetic, molecular, and vascular heterogeneity. This review describes the many forms of heterogeneity, their integrated activities, and offers some insights into how heterogeneity may be understood and studied in the future.

“Diagnostic and Prognostic Biomarkers of Luminal Breast Cancer: Where are We Now?”

“… 79 , 80 The immune system also effects ER activity, for example activation of breast cancer NFκB/STAT3 via tumor-associated macrophages can drive ER ligand-independent phosphorylation. 81 …”

“…Breast Cancer: Targets and Therapy 2023:15 528 activity, for example activation of breast cancer NFκB/STAT3 via tumor-associated macrophages can drive ER ligandindependent phosphorylation. 81 Molecular markers, including gene signatures such as Prosigna/PAM50, Endopredict (described in more detail below), breast cancer index (BCI), HOXB13/IL17BR 82 or the immunohistochemical 4 (IHC4) score 83 enable a differentiation of patients based on relapse risk after endocrine therapy and are discussed further below.…”

Reassessing Breast Cancer-Associated Fibroblasts (CAFs) Interactions with Other Stromal Components and Clinico-Pathologic Parameters by Using Immunohistochemistry and Digital Image Analysis (DIA)

“…Most of these studies were performed on classical BC histopathology, and few of them assessed CD34 fibroblasts and αSMA_CAFs related to different molecular subtypes. Despite the recently reported complex heterogeneity markers expressed by CAFs [16], CAFs' prognostic and therapeutic role is extremely limited [16,17]. Most of the studies focused on CD34/αSMA_CAF interplay in BC stroma used manual semiquantitative methods to assess immunohistochemical staining and to classify them as "present" or "absent".…”