Effect of bone marrow microenvironment on the sensitivity of breast cancer cells to antiestrogens
Hormonal therapy (HT) inhibits the growth of hormone receptor-positive (HR+) breast (BrCa) and prostate (PrCa) cancers. HT resistance frequently develops within the complex metastatic microenvironment of the host-organ (often the bone), a setting poorly recapitulated in two-dimensional (2D) culture systems. To address this limitation, we cultured HR+ BrCa/PrCa spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSCs). In 3D monocultures, antiestrogens/antiandrogens induced anoikis by abrogating the anchorage-independent growth of HR+ cancer cells but had only modest effect against tumor cells residing in the ECM niche. In contrast, BMSCs induced hormone-independent growth of BrCa/PrCa spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of the BMSC-induced hormone-independence and HT resistance in anchorage-independent cells revealed distinct, context-dependent, mechanisms. Cocultures of ZR75-1 and LNCaP with BMSCs exhibited paracrine IL-6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL-6 or JAK signaling. This paracrine IL-6/JAK/STAT3-mediated HT resistance was also confirmed in patient-derived organoids cocultured with BMSCs. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures, but also acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in non-IL-6-dependent manner. In summary, the acquisition of anchorage-independent growth in HR+ tumors is abrogated by HR blockade, but can be restored in the metastatic microenvironment through pleiotropic hormone-independent mechanisms. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help the refinement of treatment approaches. Overall design: RNA profiles of breast cancer cells in 3D cultures in the presence vs. absence of immortalized bone marrow stromal cells HS5