Many Luminal breast cancers are heterogeneous, containing substantial numbers
of estrogen (ER) and progesterone (PR) receptor-negative cells among the
ER+ PR+ ones. One such subpopulation we call “Luminobasal” is ER-, PR- and
cytokeratin 5 (CK5)-positive. It is not targeted for treatment.
To address the relationships between ER+PR+CK5– and ER–PR–CK5+ cells in
Luminal cancers and tightly control their ratios we generated isogenic pure
Luminal (pLUM) and pure Luminobasal (pLB) cells from the same parental Luminal
human breast cancer cell line. We used high-throughput screening to identify
pLB-specific drugs and examined their efficacy alone and in combination with
hormone therapy in mixed-cell tumor models.
We show that pLUM and MCF7 cells suppress proliferation of pLB cells in
mixed-cell 3D colonies in vitro and that pLUM
cells suppress growth of pLB cells in mixed-cell xenografts in vivo. High-throughput screening of 89 FDA-approved
oncology drugs shows that pLB cells are sensitive to monotherapy with the
epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib. By
exploiting mixed-cell 3D colonies and mixed-cell solid mouse tumors models we
demonstrate that combination therapy with gefitinib plus the anti-estrogen
fulvestrant constitutes a robust treatment strategy.
We propose that response to combination endocrine/EGFR inhibitor therapies in
heterogeneous Luminal cancers may improve long-term survival in patients whose
primary tumors have been preselected for appropriate biomarkers, including ER, PR,
CK5 and EGFR.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0418-6) contains supplementary material, which is available to authorized