Conceptual hierarchy of Ki67, estrogen receptor, and progesterone receptor in breast cancer cells

This preprint proposes a conceptual framework that clarifies the hierarchical relationship among Ki67, estrogen receptor (ER), and progesterone receptor (PgR) in breast cancer cells. In current clinical practice, these immunohistochemical markers are often treated as if they reflect biological phenomena at the same level. However, Ki67 represents the entry of tumour cells into the cell cycle and therefore defines the highest hierarchical level of proliferative activity. ER functions primarily as a modulator after cell-cycle entry, while PgR reflects downstream ER-dependent transcriptional activity rather than proliferation itself. By explicitly distinguishing these hierarchical layers, this work aims to provide a clearer biological interpretation of intrinsic subtypes and to highlight conceptual limitations of binary or parallel marker-based classifications currently used in clinical decision-making.