Fig. 4: The effects of cell-extrinsic and cell-intrinsic determinants in dictating breast cancer outcomes.

Part I The journey of a breast cancer patient from the development of undetectable disease and its clinical discovery (a), through its surgical removal (b) and adjuvant ET (c), to metastatic relapse and death (d). The presence of tumour lesions across the body is indicated by stars—the smaller referring to the clinically undetectable ones (no black borders), the bigger ones to the clinically detectable ones (black borders). Part II The development of an HR⁺ breast tumour lesion in the breast (primary site), comprising a mixture of ER⁺/PR⁺ and ER^–/PR^– cells (a). DTC escape from the primary site can occur early (parallel model, a) and/or late (linear model, b) during tumorigenesis (dotted pink lines), although the HR phenotype of DTCs at these stages is often unclear. Bones, lungs and liver are represented as common secondary sites for breast cancer metastases, albeit the sequential patterns of DTC spread among these organs are still elusive (green, brown and blue dotted lines). Targeted treatment for HR⁺ breast cancer patients relies on adjuvant ET. Several mechanisms of ET resistance (d)—cytostasis, ESR1 mutations and HR function regulation—contribute to DTC outgrowth. DTC disseminated tumour cell, ER oestrogen receptor, ET endocrine therapy, HR hormone receptor, PR progesterone receptor. Figure created with BioRender.com.