| Summary: | Acquired resistance to endocrine therapy is a major limiting factor for their clinical effectiveness, resulting in disease relapse and an associated poor prognosis. Acquired resistance is also associated with the development of an invasive and migratory phenotype in vitro that may promote metastatic spread in vivo of which bone is the most frequent site. However, it is not currently known whether endocrine resistance affects the ability of breast cancer cells to modulate bone cell function important in establishing bone metastases or whether a resistant phenotype alters sensitivity to agents commonly used to treat bone metastasis such as bisphosphonates. Thus, this thesis aimed to explore the bone cell modulatory function of endocrine resistant and sensitive breast cancer cells along with their sensitivity to the bisphosphonate, zoledronic acid. This thesis demonstrated that breast cancer cells were able to directly induce osteoclast differentiation from both murine and human precursor cells. Importantly, this effect was more prevalent in tamoxifen resistant and triple negative breast cancer subtypes. Our data also suggested that the breast cancer-mediated osteoclastogenic effect involved Src kinase, whilst bisphosphonates acted as anti-tumour agents in tamoxifen resistant cells through inhibition of EGFR/AKT/mTOR pathway. In conclusion, this thesis suggests that acquisition of endocrine resistance confers a bone modulatory ability to breast cancer cells that may contribute to the development of bone metastases. However, this thesis reports the novel finding that acquired endocrine resistance augments the sensitivity of breast cancer cells to bisphosphonates, thus representing an opportunity to target resistant disease clinically.
|
|---|
