Collectively, our findings attest to upregulation of ER expression (especially in the face of enhanced production of estrogen in fat depots) as an important, and previously unidentified, mechanism of obesity-accelerated BC progression, likely explaining the dichotomy of the obesity effects on the risk/poorer outcome between luminal (i.e., ER+) and non-luminal (i.e., ER−) BC subtypes. Here, ESR1 is linked to obesity due to melanocortin 4 receptor deficiency.