Dense tissue promotes aggressive cancers

August 22, 2008

New research may explain why breast cancer tends to be more aggressive in women with denser breast tissue.

Breast cancer cells grown in dense, rigid surroundings step up their invasive activities, Vanderbilt-Ingram Cancer Center investigators report in the Sept. 9 issue of Current Biology.

The findings suggest a cellular mechanism for the correlation between human breast tissue density and tumor aggressiveness. Women with increased breast density on mammograms have an increased risk for both developing breast cancer and having breast cancers with invasive characteristics.

This connection between breast density and cancer aggressiveness has begged the question of which comes first. Is the tissue denser because the tumor is more aggressive (and recruits cells that "lay down" more matrix), or is the tumor more aggressive because the tissue is denser?

"Our study shows that if you have a dense, rigid matrix, the cells will be more aggressive and invasive; it's a direct effect," said Alissa Weaver, M.D., Ph.D., assistant professor of Cancer Biology and lead author of the study.

Weaver and colleagues were interested in invadopodia - the finger-like protrusions that a cancer cell uses to drill holes in the extracellular matrix (matrix-degrading enzymes are associated with invadopodia). These structures are believed to be important for cancer invasion.

"If you have enough invadopodia, over time they'll make large holes that cells can move through to invade and metastasize," Weaver said.

Despite the intimate connection between invadopodia and the matrix, very little was known about what role the matrix might play in regulating invadopodia function. Weaver and colleagues started probing this question as part of computational math modeling project through the Vanderbilt Integrative Cancer Biology Center.

They were surprised to find that breast cancer cells cultured on a denser - and thus, more rigid - matrix had a greater number of active invadopodia than breast cancer cells cultured on a less dense matrix.

"We thought that more 'stuff' for the cells to get through was going to make it harder, so we expected to see less matrix degradation, but instead we found this interesting effect where cells actually sense the rigidity and degrade more," Weaver said.

The team examined how cells convert a sense of matrix rigidity into intracellular signals, a process called mechanotransduction.

Proteins that generate contractile forces, such as myosin "motors," are important players in mechanotransduction. Weaver and colleagues confirmed that myosin motors are involved in sparking more degradation by invadopodia in response to a rigid matrix, though the motors themselves are not present in the drilling structures.

The investigators also implicated the activities of two signaling proteins called FAK and p130Cas in the rigidity-induced invadopodia activity. These signaling proteins were present in an activated state in the invadopodia, suggesting that they are important players in this response and may represent targets for anti-invasive therapies.

Weaver said that it's exciting to find a cellular mechanism that could explain why denser breast tissue is correlated with more aggressive tumors and a poorer prognosis for patients.

"The idea that tissue rigidity leads to a more aggressive phenotype had been out there for a while," she said, "but it hadn't actually been tied to matrix degradation, which is thought to be important for metastasis and spread of cells through the body."

Because metastasis is often what makes cancers deadly, new leads on how to block it are critical, she added.
-end-
Nelson Alexander, Ph.D., Kevin Branch, Aron Parekh, Ph.D., Emily Clark, Ph.D., and Izuchukwu Iwueke, in the Department of Cancer Biology at Vanderbilt, and Scott Guelcher, Ph.D., in the Department of Chemical Engineering at Vanderbilt, contributed to the studies. The National Institutes of Health and the Vanderbilt University School of Engineering supported the research.

Vanderbilt University Medical Center

Related Breast Cancer Articles from Brightsurf:

Oncotarget: IGF2 expression in breast cancer tumors and in breast cancer cells
The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.

Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.

Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.

More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.

Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.

Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.

Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.

Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.

Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.

Read More: Breast Cancer News and Breast Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.