Overcoming retinoic acid resistance in HER2‐enriched breast cancers: role of MYC

Abstract

HER2‐enriched (HER2+) breast cancers express high levels of the growth‐promoting HER2 protein. Although these cancers are treated with the HER2‐targeted drug, trastuzumab, resistance to treatment is common. Retinoic acid (RA) is an anti‐cancer agent that has been successfully used for the treatment of leukemia and holds promise for the treatment of solid cancers, including breast cancer. The HER2 gene is frequently co‐amplified with RARA, a key determinant of RA sensitivity in breast cancers. It seems surprising, therefore, that HER2+ breast cancers are refractory to RA treatment. Here, we show that MYC mediates RA resistance by suppressing the expression of cellular retinoic acid binding protein 2 (CRABP2), resulting in RARα inactivation. CRABP2 is an intracellular RA transporter that delivers RA to the nuclear receptor RARα for its activation. Our results indicate that response to RA is enhanced by MYC depletion in HER2+ breast cancer cells and that RA treatment enhances trastuzumab responsiveness. Our findings support the use of RA and trastuzumab for the treatment of subsets of patients with breast cancers that are HER2‐RARα co‐amplified and have low levels of MYC.