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Breast cancer study 'identifies tumour-causing enzyme'
MRI scan of breast cancer
Breast cancers are surrounded by stiffer, more fibrous tissue
Scientists have identified an enzyme that is crucial for turning breast tissue into tumours, according to a study published in the journal Cell.
The Institute of Cancer Research says blocking the enzyme lysyl oxidase (LOX) reduced the size and frequency of tumours in mice.
They say LOX stiffens collagen, a major component of the supportive tissue in the breast.
A cancer charity said the study added to knowledge about how tumours develop.
The supportive tissue surrounding cancer cells is shaped differently to healthy tissue as well as being stiffer and more fibrous.
These properties have helped doctors to detect breast cancers, but until now scientists have not known what was causing these changes.
'Clear physical change'
The team at the Institute for Cancer Research, using mice, found that LOX caused the collagen to change in a process known as cross-linking, which makes the tissue more fibrous.
The next stage will be to test whether LOX has the same effect in humans but it is likely to be some time before any potential new treatment is developed
Dr Alexis Willett
Breakthrough Breast Cancer
Higher levels of LOX increased the levels of collagen in mammary glands, made the tissue stiffer and correlated with a higher number of tumours invading the breast tissue.
When the team used chemicals or an antibody to block the enzyme, they found collagen in the mammary glands contained fewer cross-links and was less fibrous.
The tissue also contained fewer, smaller tumours and they were less aggressive.
Dr Janine Erler from the Institute of Cancer Research, who led the research, said the study showed that stiffening of the breast tissue controlled by enzymes such as LOX was a key factor in cancer development. These enzymes could be a promising candidate drug target, she added.
"The enzyme triggers a clear physical change in breast tissue and, if we could stop this happening, we expect it would slow the growth of any cancers that did develop and make them easier to eradicate."
Professor Valerie Weaver of the University of California in San Francisco, who was also part of the team, said: "This study may also help explain why the rate of breast cancer increases dramatically with age - aged tissues are stiffer and contain higher levels of abnormal collagen cross-links.
"I'm cautiously optimistic. We still have a lot more work to do, but this is certainly exciting."
Dr Alexis Willett, head of policy at Breakthrough Breast Cancer, said: "This early stage research in cells and mice increases our understanding of how breast cancers develop and grow and suggests that enzymes such as LOX could be a potential target in the treatment of breast cancer.
"The next stage will be to test whether LOX has the same effect in humans, but it is likely to be some time before any potential new treatment is developed."
Cell, Volume 139, Issue 5, 891-906, 19 November 2009
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
Kandice R. Levental1, 10, Hongmei Yu2, 10, Laura Kass2, Johnathon N. Lakins2, Mikala Egeblad4, 11, Janine T. Erler3, 12, Sheri F.T. Fong5, Katalin Csiszar5, Amato Giaccia3, Wolfgang Weninger6, Mitsuo Yamauchi7, David L. Gasser8 and Valerie M. Weaver1, 2, 4, 9, Go To Corresponding Author,
1 Department of Bioengineering and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA
2 Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
3 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
4 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA
5 Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96822, USA
6 Immunology Program, Wistar Institute, Philadelphia, PA 19104, USA
7 Dental Research Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
8 Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA
9 Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
10 These authors contributed equally to this work
11 Present address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
12 Present address: Section of Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, UK
Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.
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