Protein May Regulate Hormone Sensitivity in Breast Cancer || NCI Cancer Bulletin for November 15, 2011 - National Cancer Institute

Protein May Regulate Hormone Sensitivity in Breast Cancer

New research indicates that a protein called TWIST plays a key role in the aggressiveness and progression of breast cancers by regulating estrogen receptor (ER) expression. This discovery may ultimately open the door to new treatments for ER-negative breast cancers, which are more aggressive and harder to treat than ER-positive breast cancers, said the researchers who led the study. The findings, from investigators at the Johns Hopkins University School of Medicine and the University Medical Center Utrecht in the Netherlands, were published online November 7 in Oncogene.

Unlike ER-positive breast cancers, which rely on estrogen to grow and can often be successfully treated with drugs that block the action of this hormone, ER-negative breast cancers do not need estrogen to grow. According to the new research, the loss of the ER in TWIST-expressing cells causes the cells to grow independently of estrogen and to resist the effects of antiestrogen therapy.

Previous research had shown that the TWIST gene is overexpressed in some high-grade breast cancers and may play a role in breast cancer development. To investigate how TWIST may function, the researchers examined ER expression levels in breast cancer cell lines with varying levels of TWIST expression. This analysis showed that levels of TWIST protein were inversely related to levels of ER mRNA and protein. The investigators then demonstrated that TWIST represses the ER gene by preventing its transcription.

Subsequent experiments showed that breast cancer cells that express high levels of TWIST were able to grow in culture and to form tumors in mice in the absence of estrogen. These TWIST-expressing cells and tumors continued to grow even in the presence of the antiestrogens tamoxifen and fulvestrant. When the researchers used a technique to reduce TWIST levels in these cells, the cells produced substantially more ER and became sensitive to estrogen and antiestrogens.

To determine whether the inverse relationship between TWIST and ER that was seen in cell lines also holds true in human breast tumors, the investigators assessed TWIST and ER expression levels in 73 primary tumors. They found a statistically significant inverse correlation between TWIST and ER mRNA levels in grade 1 and 2 (but not grade 3) tumors.

“Now that we know that TWIST plays a major role in controlling estrogen resistance in breast cancer, we can investigate the value of antiTWIST therapies,” said senior author Dr. Venu Raman in a press release. For example, the authors suggest, such therapies might be able to render ER-negative cancers ER-positive, making them dependent on estrogen for growth and responsive to antiestrogen therapies.

NCI Cancer Bulletin for November 15, 2011 - National Cancer Institute