CAXII Is a Surrogate Marker for Luminal Breast Tumors Regulated by ER and GATA3

Estrogen receptor alpha (ERα) expression in ~2/3 breast tumors selects patients for hormonal therapies. Tumors negative for ERα but positive for the progesterone receptor (PR, encoded by PGR) have also been candidates for ER-targeting therapies, as PR expression may reflect undetected ER activity. Conversely, PR^- status in ER⁺ tumors predicts a worse therapeutic response. Our analysis of breast tumor transcriptome datasets, however, revealed that in tumors with lower PGR expression, the clinical PR status does not correlate accurately with the expression of ESR1 or of ER target genes, including PGR itself. We identified carbonic anhydrase 12 (CA12) as an estrogen target gene better correlated with ESR1 than PGR, reflecting CA12 regulation by both ERα and the luminal factor and upstream ESR1 regulator GATA3. Immunostaining supported strong positive correlations at the protein level with ERα and GATA3 in a cohort of 118 tumors. Most ER⁺PR^- tumors expressed CAXII at levels similar to those of ER⁺PR⁺ tumors, consistent with observations in tumor transcriptome datasets and with active estrogenic signaling in some ER⁺PR^- breast cancer cell lines. The few ER^-PR⁺ tumors did not express CAXII or the other luminal markers FOXA1 and GATA3. Overall, CAXII is a luminal marker that can help interpret ER status in single ER/PR positive tumors.