New therapies aimed at breaking the linkage between obesity and breast cancer

New therapies aimed at breaking the linkage between obesity and breast cancer is a Research Project for the Research Group, under the New therapies aimed at breaking the linkage between obesity and breast cancer.

Project Leader

kristys-imageDespite currently being the first line therapy for hormone receptor-positive postmenopausal breast cancer, aromatase inhibitors also cause side effects, which impact compliance. Therapies targeting aromatase specifically within the adipose would be provide a tolerable alternative to current treatments, leaving sites such as bone and brain unaffected and protecting quality of life. Our findings demonstrating the inhibitory nature of the LKB1/AMPK pathway on aromatase expression within the breast has sparked interest in using metformin, the most commonly prescribed anti-diabetic drug, to treat and possibly prevent oestrogen-dependent cancers. This stems from our findings that metformin activates AMPK and metformin decreases the incidence of cancer in patients with type II diabetes. This work has also motivated the search for novel modulators of aromatase in the context of obesity and oestrogen-dependent cancer.

Metformin to treat and prevent oestrogen-dependent cancer, and complications of endocrine therapy

Through previously awarded Victorian Breast Cancer Research Consortium funding and in collaboration with endocrinologists, medical oncologists, breast cancer surgeons and several cosmetic surgeons, we will study the effect of metformin on aromatase expression and adipose oestrogen levels, within the breasts of healthy mid-life women and women with breast cancer. These studies are important as aromatase inhibitors, despite being efficacious at halting disease progression, cause a number of side effects due to global inhibition of oestrogen biosynthesis. Our groups findings, as well as observational data from diabetics taking metformin, suggest that metformin will decrease oestrogen production in the breast without inhibiting bone oestrogen biosynthesis and hence would inhibit tumour growth without bone loss and arthralgia, the leading causes for discontinuing aromatase inhibitor use in women with breast cancer.

The use of endocrine therapy like tamoxifen in postmenopausal women with breast cancer increases the risk of endometrial hyperplasia and cancer. There is therefore a need to find tolerable therapies to limit this devastating side-effect of currently used endocrine treatments. In NHMRC-funded work through a collaboration with Profs Davis and Bell (Alfred Hospital) we will investigate themechanisms by which metformin may prevent development or induce regression of endometrial hyperplasia in these women. Positive findings would provide a strong basis for further research into the use of metformin to prevent and possibly treat endometrial hyperplasia and cancer.

Ghrelin, a new breast-specific aromatase inhibitor

A number of peptide hormones altered in obesity act via AMPK. One such factor is ghrelin, an orexigenic hormone produced by the gut that activates AMPK in the hypothalamus. We have recently demonstrated that ghrelin inhibits aromatase expression and activity. As part of our National Breast Cancer Foundation-funded research, we will test ghrelin receptor agonists in vitro and in viv breast cancer cell growth o understand their effect on aromatase and oestrogen production.

Collaborators

MIMR-PHI collaborator Professor Evan Simpson
University of Melbourne collaborator Professor John Furness
Monash Health collaborators Dr Vinod Ganju, Mrs Jane Fox
Peter MacCallum Cancer Centre collaborator Dr Kara Britt
Alfred Hospital collaborator Prof Susan Davis
Turku University collaborator Prof Sari Makela
MIMR-PHI collaborator Prof Lois Salamonsen