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.

Keywords: breast cancer; drug resistance; endocrine therapy; heterogeneity; systems biology.

Figure 1

Illustration depicting spatial and temporal heterogeneity. (A) A primary tumor with heterogeneous population of treatment sensitive and resistant cancer cells along with tumor associated cells. Treatment over time may allow expansion of resistant cells. (B) Primary tumors metastasize over time to produce metastatic tumors in different organs with different cell composition (temporal heterogeneity) that may also lead to intra-host heterogeneity.

Figure 2

An illustration depicting the effects of cancer associated fibroblasts (CAF) cells on cancer cells through various mechanisms. (A) CD146 negative (CD146neg) CAF activate EGFR, HER2, and IGFR in breast cancer cells that promotes tamoxifen resistance whereas GPR30 positive (GPR30+) CAF cells induce tamoxifen resistance by upregulating MEK/ERK and PI3K/AKT signaling. (B) CD63 positive (CD63+) CAF promote tamoxifen resistance by downregulating ER and PTEN mediated by exosomes containing miR22. (C) Low caveolin-1 (CAV-1) expression in CAF upregulates TIGAR that protects cancer cells by inhibiting aerobic glycolysis, apoptosis and autophagy. (D) CD10 positive (CD10+) and GPR77 positive (GPR77+) CAF induces chemoresistance by sustained secretion of IL-6 and IL-8 and enrichment of stromal cancer stem cells.