St Vincent's Institute

Epithelial Mesenchymal Plasticity in Breast Cancer Progression

Group Leaders: Prof Erik Thompson, Dr Mark Waltham Team Members: Dr Bryce van Denderen, Dr Honor Hugo, Dr Eva Tomaskovic-Crook, Mr Tony Blick, Ms Razan Wafai (PhD student), Ms NPA Devika Gunasinghe (PhD student), Mr Anthony Tsachtsidis (PhD student), Mr Cletus Pinto (PhD student), Mr. Edwin Widodo (PhD student), Ms Eliza Soo (PhD student), Ms Hilda Lau (Hons student)

Several lines of research into EMP in breast cancer are ongoing. We continue to characterise the molecular processes associated with EMP in the PMC42 and PMC42-LA cell lines, and in MDA-MB-468 human breast cancer cells, which can also be studied in vivo. Gene array studies in these cell lines for mRNA splice variants and micro RNA are performed in parallel with bioinformatics studies using publicly available, genome-wide data on breast cancer cell lines and tumours (see Blick et al., 2008, 2010). Another research focus is the analysis of EMP in circulating (CTC) and disseminated (DTC) tumour cells, which are found in the blood and bone marrow, respectively, of cancer patients. Collectively, these studies provide leads towards new diagnostics and therapeutics for breast cancer and underpin our commitment to the National Breast Cancer Foundation supported EMPathy Breast Cancer Network headed by Prof Thompson (http://www.mtci.com.au/TEMTIA/EMPathy.html).

Interplay between hypoxia, c-myb, oestrogen and Snail2 during epithelial mesenchymal transitions (EM

Group Leaders: Dr Honor Hugo, Prof Erik Thompson

Team Members: Ms Hilda Lau (Honours student)

Unrestrained tumour growth with a poorly organized blood supply results in hypoxia, a critical microenvironmental determinant for metastasis. The transcription factor Snail2, a well-known inducer of EMT, is overexpressed in invasive breast cancer and is induced by hypoxia. Snail2 and the proliferation gene c-myb were shown to be inversely expressed across 51 luminal, basal A and basal B breast cancer cell lines, however no direct, functional link has been made between Snail2 and c-myb in primary tumour invasion. We hypothesize that the effects of hypoxia (the induction of EMT and a slowing of proliferation) are mediated in part by Snail2 directly repressing c-myb. Hence, restored, normoxic conditions at secondary tumour sites (soft tissues and bone) would result in the re-expression of c-myb and, through the reverse transition (MET), the establishment of a metastasis.

In breast cancer, 70% of tumours are oestrogen receptor (ER) positive, where proliferation is driven by the sex hormone oestrogen and can be blocked by tamoxifen. Breast cancer metastases are frequently ER-alpha negative and cannot be treated with tamoxifen. We propose that restoring ER-alpha expression will restore tamoxifen sensitivity, and thus present a mechanism for significantly improving the treatment of advanced breast cancer. Because oestrogen directly induces c-myb transcriptional elongation, which is necessary for the proliferation of ER-alpha positive breast cancer cells, we will also investigate the relationships between ER-alpha and gene products implicated in EMT.

Matrix Metalloproteinases in Breast Cancer Growth and Progression

Group Leaders: Prof Erik Thompson, Dr Mark Waltham, Dr Manisha Shah Team Members: Mr Dexing Huang, Mr Tony Blick, Ms Bryna Chow

MMP13 has emerged as a promising therapeutic target in breast cancer and highly specific inhibitors have been developed that do not cause musculoskeletal side effects, which has plagued the clinical trials of other MMP inhibitors. Our ongoing studies with MMP13-deficient mice have confirmed a role for MMP13 in breast cancer growth at the primary site and in the osteolytic lesions that form at bone metastases, and also implicated MMP13 in breast cancer angiogenesis. Our collaborator Prof Chris Overall (University of British Columbia, Vancouver, Canada) has identified novel substrates of MMP13 that may serve as biomarkers for MMP13 activity. We plan to perform clinically relevant studies of MMP13 inhibition in combination with current breast cancer treatments using well established, syngeneic mouse mammary cancer models. We will elucidate the role of MMP13 in breast cancer lymph/angiogenesis, and develop biomarkers suitable for monitoring MMP13 activity in breast cancer and in MMP13-targeted clinical trials. Our studies have potential clinical application to primary and metastatic breast cancer, and likely also other bone-associated cancers and pathologies.

Molecular and cellular basis of mammographic density in breast cancer

The Invasion and Metastasis Unit plays an active role in a large collaborative research program including all current VBCRC laboratories, surgeons, pathologists and radiologists from St. Vincent’s Hospital, A/Prof Lilian Soon (University of Sydney), and Dr Karen Sui and Prof Rob Henry (Australian Synchrotron, Melbourne), seeking to identify the molecular and cellular underpinnings of the increased breast cancer risk associated with MD, a familial trait. Since 2007, we have coordinated with the relevant clinical collaborators the precise accrual of high MD and low-MD material from mastectomies at St. Vincent’s Hospital. Gene array and histologic analyses of these tissues have been carried out by PhD student Joyce Lin (University of Melbourne, Dept. Pathology). VBCRC funding is in place to extend these analyses to discordant monozygous twins.