Seed, soil and secreted hormones: potential interactions of breast cancer cells with their endocrine/paracrine microenvironment and implications for treatment with bisphosphonates.

The process of formation of metastasis is undoubtedly inefficient, with the majority of disseminated tumour cells perishing in their metastatic environment. Their ability to survive is determined by their intrinsic abilities, with emerging evidence of the importance of cancer stem cells possessing self propagating potential, but also the interaction with the premetastatic niche, which may either help or hinder their formation into micrometastasis, thus influencing recurrence and survival in breast cancer patients. Use of the bone targeted agents bisphosphonates in the adjuvant setting has been extensively studied in large clinical trials, and demonstrated an interesting interplay with the endocrine microenvironment, with postmenopausal women or premenopausal women receiving ovarian suppression therapy gaining a survival advantage compared to pre/perimenopausal women. The interaction between the endocrine hormones and the paracrine TGFβ growth factors may provide an explanation for the differences seen according to ovarian function in the response to bisphosphonates. In this review the evidence of interplay between ovarian endocrine hormones, TGFβ paracrine growth factors and bisphosphonates will be presented, and subsequent influence on breast cancer cells in the bone pre-metastatic niche hypothesised.