3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response.

BACKGROUND: The 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. METHODS: A 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. RESULTS: Breast 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. CONCLUSION: These 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.

Pro-metastatic tumor-stroma interactions in breast cancer.

The vast majority of breast cancer-related deaths are due to metastatic disease. Reciprocal and complex interactions between epithelial tumor cells and the various components of the tumor microenvironment influence tumor progression and metastases although the molecular mechanisms underlying these metastasis-promoting effects are not fully characterized. Identifying and understanding pathways of tumor-stroma cross-talk are likely to lead to the development of novel prognostic biomarkers for metastasis and strategies to prevent metastasis at its earliest stages, resulting in improved patient outcomes.

Exemestane in postmenopausal women with early or advanced breast cancer: a review.

IMPORTANCE OF THE FIELD: Inhibition of the aromatase enzyme in postmenopausal women reduces levels of estrogens, which is of therapeutic value in hormone-sensitive breast cancer. Exemestane is a third-generation steroidal irreversible inactivator of the aromatase enzyme used in early and advanced breast cancer for the treatment of postmenopausal women with estrogen-receptor-positive disease. AREAS COVERED IN THIS REVIEW: The scientific literature on exemestane, including published articles and abstracts, was searched from 1988 to the present, and the most significant results are included in the review. WHAT THE READER WILL GAIN: The review outlines the pharmacological characteristics of exemestane and the evidence supporting its use in the treatment of postmenopausal women with early or advanced estrogen-receptor-positive breast cancer. TAKE HOME MESSAGE: Exemestane is an effective and well-tolerated aromatase inhibitor with a defined role in early-stage breast cancer following 2 - 3 years of adjuvant treatment with tamoxifen. Exemestane also has a role in the sequence of hormonal agents employed to control advanced hormone-sensitive breast cancer, in which clinicians may exploit its partial lack of cross-resistance with nonsteroidal aromatase inhibitors.

Long-term efficacy and safety of anastrozole for adjuvant treatment of early breast cancer in postmenopausal women.

For more than 20 years, tamoxifen has been the gold standard for the adjuvant treatment of postmenopausal women with hormone-responsive early breast cancer. However, recent randomized trials have shown efficacy and tolerability benefits with the third-generation aromatase inhibitor anastrozole, resulting in an increased use of this agent in the adjuvant setting. Data on anastrozole's long-term efficacy and tolerability are therefore of interest in clinical practice and will be reviewed here, especially in the light of the 100-month analysis of the ATAC (Anastrozole, Tamoxifen Alone or in Combination) trial.