Abstract
BackgroundThe Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity.MethodsA 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting.ResultsBreast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response.ConclusionThese data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2377-z) contains supplementary material, which is available to authorized users.
Highlights
The Human Epidermaal Growth Factor Receptor 2 (Her2) receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis
Recovery of cells from 3D culture for experimental analysis Cells were recovered from the 3D cultures for counting, immunocytochemical analysis or Western blotting using a modification of a previously reported method [18] and Additional file 2: S1B
Breast cancer cells growing in 3D culture retain characteristics of 2D cultures In this study we set out to investigate the effects of 3D culture in a matrix-enriched environment on the therapeutic sensitivity of two estrogen receptor (ER)+/Her2+ breast cancer cell models
Summary
The Her receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. Increasing evidence points to the interplay between the tumour and its surrounding microenvironment as a significant determinant of therapeutic sensitivity and response [5, 6] with tumour-stroma interactions demonstrated to influence tissue response to ionizing radiation [7], chemotherapeutics and more recently targeted agents [8, 9]. The migration of fibrosarcoma cells in 2D culture is decreased by doxorubicin chemotherapy whereas this effect is completely abolished when grown in the context of a 3D collagen-rich matrix [11]
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