Table 1 Evidence supporting the origin of ER-negative breast cancers from ER-positive precursors

Epidemiological

Increased oestrogen exposure mediated by ER is a risk factor for all breast cancers

Prophylactic oophorectomy in BRCA1 mutation carriers reduces all breast cancers

ADH (>90% ER-positive cells) is a strong risk factor for all breast cancers

The proportion of ER-negative breast cancers increases with time (tumour progression)

Histological/pathological

All early premalignant breast lesions are strongly ER positive

ER-positive precursors associated with ER-negative cancers in same breast/patient

Molecular

MAPK activation reversibly transforms ER-positive to ER-negative breast cancers

Methylation ER promoter reversibly transforms ER-positive to ER-negative breast cancers

Apocrine metaplasia may reversibly transform ER-positive to ER-negative breast cancers