Tumor microenvironmental growth factors induce long-term estrogen deprivation resistance in breast cancer

• Published in: Breast cancer (Tokyo, Japan) Vol. 26; no. 6; pp. 748 - 757
• Main Authors: Tsuboi, Kouki, Uematsu, Chiyuki, Yamaguchi, Yuri, Niwa, Toshifumi, Hayashi, Shin-ichi
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.11.2019; Springer
• Subjects: Analysis; Aromatase Inhibitors - adverse effects; Aromatase Inhibitors - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer Research; Care and treatment; Cell Survival - drug effects; Development and progression; Drug Resistance, Neoplasm; Epidermal Growth Factor - metabolism; Estrogen; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Fulvestrant; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Medicine; Medicine & Public Health; Mitogen-Activated Protein Kinases - metabolism; Oncology; Original Article; Phenols; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Postmenopausal women; Receptor, ErbB-2 - metabolism; Surgery; Surgical Oncology; Thiazoles - pharmacology; Transfection; Tumor Microenvironment; Breast cancer; Aromatase inhibitor; Tumor microenvironment; Hormonal therapy resistance
• ISSN: 1340-6868; 1880-4233
• DOI: 10.1007/s12282-019-00978-z

Background Hormonal therapy is an effective treatment for luminal-like breast cancer. Aromatase inhibitor (AI) is widely used for estrogen receptor-positive, postmenopausal breast cancers. However, resistance is occurred and becomes a serious clinical concern. In general, progression of cancer strongly depends on tumor microenvironment, which may, therefore, also contribute to the development of AI resistance. Methods We evaluated tumor microenvironment-derived factors with respect to AI resistance using typical estrogen receptor-positive breast cancer cell lines. We established tumor microenvironment-dependent AI-resistant models and elucidated the underlying mechanisms. Results T-47D cells had a higher dependence on microenvironment-derived factors, such as estrogen or growth factors, for survival than MCF-7 cells. We, therefore, evaluated tumor microenvironment growth factors with respect to AI resistance using T-47D cells. We established three resistant cell lines (V1, V2, and V3) that survived estrogen deprivation and growth factor-supplemented conditions. These cell lines were deficient in estrogen receptor α expression and estrogen-dependent growth. Among six representative growth factors, epidermal growth factor was the most influential. In these models, HER2 protein was overexpressed without gene amplification and intracellular phosphorylation pathways were activated compared to parental cell lines. Molecular targeting inhibitors revealed that V1 and V2 primarily rely on the PI3 K pathway for survival, whereas V3 relies on the MAPK pathway. Conclusions This study demonstrates the importance of tumor microenvironment-derived factors for the development of AI resistance. These resistant models did not utilize the same resistance mechanism, suggesting that flexible strategies are essential in conquering resistance.