School of Medical Sciences


Assessing the effectiveness of small molecule inhibitors on breast cancer cell growth

One million women worldwide are diagnosed annually with breast cancer, of which 65% have estrogen receptor positive cancer.

Breast cancer growth in its early stages is known to be driven by steroid hormone oestrogen, and one of the main methods of treating breast cancer apart from surgery is to block the growth promoting action of this hormone either by blocking the downstream action with antioestrogens such as tamoxifen, or by reducing the concentration of circulating oestrogen through oophorectomy or treatment with an aromatase inhibitor. Both types of treatment can be followed by the emergence of aggressive tumours that pose a major barrier to successful management. We have grown the MCF-7 breast cancer cell line in culture for relatively long periods either in the presence of tamoxifen to block oestrogen action, or in the absence of oestrogen to mimic the action of oophorectomy or treatment with aromatase inhibitors. We are using these lines to investigate new types of therapy for emerging forms of breast cancer that are resistant to antioestrogens and aromatase inhibitors.

Current research


breastcan_fig004

Our current research is focused on assessing small molecule inhibitors such as PI3K/mTOR inhibitors on their effectiveness in breast cancer cell growth using the estrogen receptor positive cell line models.

We also focus on determining the mechanism responsible of cyclohexanone derivatives responsible for their suppression of breast cancer cell growth.

In addition, we have several potential topoisomerase posions in our drug discovery program aimed at developing therapeutic strategies for breast cancer.

 

Collaborators:

A/Prof Rhonda Rosengren, Otago University

Dr. Lesley Larsen, New Zealand Institute for Crop and Food Research

Selected recent publications


Leung E, Rewcastle GW, Joseph WR, Rosengren RJ, Larsen L, Baguley BC. Identification of cyclohexanone derivatives that act as catalytic inhibitors of topoisomerase I: effects on tamoxifen-resistant MCF-7 cancer cells. Invest New Drugs, 2011 (Epub)10.1007/s10637-011-9768-4

Leung E, Kim JE, Rewcastle GW, Finlay GJ, Baguley BC. Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells. Cancer Biol Ther. 2011;11(11):938-46. (PMID: 21464613)

Leung E, Kannan N, Krissansen GW, Findlay MP, Baguley BC. MCF-7 breast cancer cells selected for tamoxifen resistance acquire new phenotypes differing in DNA content, phospho-HER2 and PAX2 expression, and rapamycin sensitivity. Cancer Biol Ther. 2010; 9(9):717-24. (PMID: 20234184)