Researchers find molecular 'Achilles heel' for half of breast cancer tumours

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Washington, January 16 : Scientists in the Unites States have shown that a protein known as cyclin D1 may be the Achilles heel for estrogen receptor positive (ER+) breast tumours, which is the most common type of breast cancer.

Researchers at Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, say that their findings support testing an experimental class of drugs that aim to inhibit the cyclin D1 protein in women with ER+ breast cancers.

"Everyone knows that cyclin D1 is a huge player in breast cancer, but no one has shown what happens when cyclin D1 is absent at the same time that the estrogen receptor is being over-expressed on tumours. Now we know the answers, and we hope these insights help further our understanding and treatment of breast cancer," said the study's lead author, Maria Silvina Frech, who is currently a postdoctoral researcher at the National Cancer Institute but who worked on the study at Georgetown.

The researchers insist that their findings provide additional molecular support for their use in breast cancer.

"These findings give insight into how drugs that indirectly inhibit cyclin D1 function, either those in testing or ones to be developed, might help a significant number of women with breast cancer," said Dr. Priscilla Furth, a professor at the Lombardi Comprehensive Cancer Center who is the study's senior investigator.

A study had shown in 2005 that over expression of Era - the main estrogen receptor subtype that mediates cell growth and is the major player in ER+ breast cancer - in mice resulted in the development of the earliest form of breast cancer, ductal carcinoma in situ (DCIS).

The researchers later found that cyclin D1 was over expressed in those lesions, but not in the surrounding normal tissue.

"Once the cancer process begins, cyclin D1 starts being over-expressed. This was an exciting finding, but it was not clear what the precise role cyclin D1 plays in ER+ cancer," Frech said.

With a view to finding what the protein was doing in these breast tumors, Frech and Furth's team created an animal model that both over-expressed ERa and lacked cyclin D1.

They were expecting to see a decreased incidence in DCIS in the animals, but what they actually found was that they completely lacked the mammary gland tissue that normally encases breast milk ducts.

"This was very surprising. Most of the cells that usually make up the gland were absent, replaced by other structural tissue that shouldn't be there," Frech said.

The researchers eventually discovered that when cyclin D1 was deleted, levels of another major cyclin family member, known as cyclin E, were increased. Over-production of cyclin E in the developing gland of these ERa over expressing mice led to DNA damage and cell death.

Frech said that it was yet to be determined whether the same situation would hold true in advanced cancers treated with agents that inhibit cyclin D1 function.

The researchers have also discovered that while cyclin D1 was not necessary for maintenance of normal breast cells, it was essential for the proliferation of abnormal mammary gland cells. This differential use of cyclin D1 seems to be unique to early breast cancer, they add.

"That supports the idea that reducing cyclin D1 in breast cancer cells would not harm normal cells," she said.

The findings have been reported in the journal Oncogene.

ANI

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