Biological & Clinical Significance of Caveolin in Human Breast Cancer.
Lead Research Organisation:
Institute of Cancer Research
Department Name: Division of Breast Cancer Research
Abstract
Caveolin-1 is emerging as a key molecule in breast cancer. Interestingly, previous studies have found that caveolin-1 can both help and hinder the formation and spread of breast cancer. Caveolin-1 also has an impact on how cancers respond to particular treatments. However, its exact role is not fully understood. In this study, a combination of molecular techniques will be used to assess the nature, expression and role of caveolin-1 in a large number of breast cancers of different types. Working within a team of experts at one of the worldâs leading cancer hospitals and research institutes, our project intends to find out if alterations in caveolin-1 and its associated processes can be used to predict the outcome of patients with breast cancer. We will undertake detailed experiments to investigate how caveolin-1 works inside breast cancer cells and the impact it has on other processes important for the development and progression of cancers. Improvements in our understanding may allow better selection of treatments for particular patients. This project will also determine if caveolin-1 can be directly targeted by newer treatments. Women who are particularly likely to benefit are those who do not respond to currently used hormonal or biological treatments.
Technical Summary
Caveolae are specialised invaginations of the cell membrane with diverse biological roles. Caveolin-1 (Cav-1) is the principal constituent protein and its misexpression has been implicated in the development and progression of several human tumours, including breast cancer (BC). The mechanism by which Cav-1 contributes to the malignant phenotype, however, remains controversial. Intriguingly, Cav-1 has been reported to have both tumour suppressor activity and oncogenic function. The objectives of this proposal are to evaluate the biological and clinical significance of Cav-1 in human BC. We aim to address fundamental questions regarding the role of the Cav-1 gene (CAV1) in the pathogenesis and progression of BC, in particular, the frequency of gene mutations and their implications and interactions between Cav-1 and steroid receptor/growth factor signalling pathways which may offer utility as a biomarkers for guiding treatment selection or potential therapeutic exploitation.
The frequency of Cav-1 mutations will be determined using state of the art mass-array sequencing technology (Sequenom), validated by conventional Sanger sequencing, to assess micro-dissected tumour tissue from a well characterised large cohort of BC patients with detailed follow-up. Transfection and RNA interference (RNAi) silencing experiments for Cav-1 will then be used to evaluate the molecular implications of such mutations in particular subtypes of BC, namely hormone receptor positive and negative tumours. Interactions between Cav-1 and steroid receptor/growth factor signalling pathways will be investigated, with particular emphasis on endocrine sensitivity and mechanisms of resistance in oestrogen receptor (ER) positive BC cell lines. The impact of commonly used endocrine therapies, such as tamoxifen, aromatase inhibitors and oestrogen receptor antagonists will be evaluated in vitro. Cav-1 expression is strongly associated with basal-type BCs. Hence, we will investigate the Cav-1-dependent survival pathways and their utility for treatment selection or potential therapeutic exploitation in ER negative BC cell lines.
This study offers an opportunity to define the biological role of Cav-1 and its associated mutations in human BC. Whilst the precise roles of Cav-1 in cancer remain elusive and the literature is somewhat conflicted, its relevance to human BC certainly warrants further study. Scrutiny of Cav-1 associated signalling pathways and cross-talk between them may inform the molecular profiling of breast tumours and permit insights into the non-classical regulation of steroid / growth factor signalling. Translational opportunities include the potential for manipulation of endocrine sensitivity / resistance in hormone receptor positive cases and the therapeutic exploitation of Cav-1-dependent pathways in hormone insensitive tumours.
The frequency of Cav-1 mutations will be determined using state of the art mass-array sequencing technology (Sequenom), validated by conventional Sanger sequencing, to assess micro-dissected tumour tissue from a well characterised large cohort of BC patients with detailed follow-up. Transfection and RNA interference (RNAi) silencing experiments for Cav-1 will then be used to evaluate the molecular implications of such mutations in particular subtypes of BC, namely hormone receptor positive and negative tumours. Interactions between Cav-1 and steroid receptor/growth factor signalling pathways will be investigated, with particular emphasis on endocrine sensitivity and mechanisms of resistance in oestrogen receptor (ER) positive BC cell lines. The impact of commonly used endocrine therapies, such as tamoxifen, aromatase inhibitors and oestrogen receptor antagonists will be evaluated in vitro. Cav-1 expression is strongly associated with basal-type BCs. Hence, we will investigate the Cav-1-dependent survival pathways and their utility for treatment selection or potential therapeutic exploitation in ER negative BC cell lines.
This study offers an opportunity to define the biological role of Cav-1 and its associated mutations in human BC. Whilst the precise roles of Cav-1 in cancer remain elusive and the literature is somewhat conflicted, its relevance to human BC certainly warrants further study. Scrutiny of Cav-1 associated signalling pathways and cross-talk between them may inform the molecular profiling of breast tumours and permit insights into the non-classical regulation of steroid / growth factor signalling. Translational opportunities include the potential for manipulation of endocrine sensitivity / resistance in hormone receptor positive cases and the therapeutic exploitation of Cav-1-dependent pathways in hormone insensitive tumours.