Breast cancers that are hormone-receptor-positive usually respond to hormonal therapy medicine (tamoxifen or an aromatase inhibitor). The study reviewed here is early research done in a lab on individual cells, not on people. The researchers found that hormone-receptor-positive invasive lobular breast cancer cells may not respond or may stop responding to tamoxifen because the cells develop a protein receptor that stops tamoxifen from blocking estrogen.
Invasive lobular carcinoma (ILC) is breast cancer that begins in the milk-producing lobules that empty into ducts that carry milk to the nipple. ILC is the second most common type of invasive breast cancer. Invasive ductal carcinoma (IDC), which begins in the ducts that carry milk from the lobules to the nipple, is the most common type of invasive breast cancer.
Both invasive lobular and invasive ductal cancer cells usually have hormone receptors, which make these cancers likely to be hormone-receptor-positive. ILC cells are more likely than IDC cells to have hormone receptors. But invasive lobular breast cancer is more likely to have a poor response or no response at all to tamoxifen compared to invasive ductal breast cancer.
This study suggests that ILC's lack of response to tamoxifen might be because some ILC cells produce too many receptors that act like estrogen receptors but aren't really estrogen receptors. These receptors are called estrogen-related receptor gamma (ERR-gamma). ERR-gamma appears to block tamoxifen's effect on estrogen receptors. The genes HMGCS2 and FASN may help make ILC cells produce too many ERR-gamma.
Identifying receptors such as ERR-gamma and the genes that make cells produce these receptors can help researchers and doctors working to find new, better ways to treat breast cancer that doesn't respond well or at all to available treatments. Based on this research, ERR-gamma, as well as the HMGCS2 and FASN genes, may guide the development of new targeted therapies. This type of research led to the development of the targeted therapy Herceptin (chemical name: trastuzumab). Researchers first discovered that certain breast cancer cells produce too many HER2-neu receptors. These cancers are known as HER2-positive cancers. Scientists then began trying to develop medicine that could target the HER2-neu receptor and Herceptin was the result.
Stay tuned to Breastcancer.org for the latest research findings that may lead to new, better ways to prevent, diagnose, and treat breast cancer.
WASHINGTON, Oct. 30 (MedPage Today) -- Tamoxifen resistance in invasive lobular breast cancer may arise from overexpression of an "orphan" nuclear receptor that is structurally similar to the estrogen receptor.
Overexpression of estrogen-related receptor (ERR)-gamma blocked the growth-inhibiting effects of tamoxifen in lobular breast cancer cell lines, Rebecca B. Riggins, Ph.D., of Georgetown University, and colleagues reported online in the Nov. 1 issue of Cancer Research.
Use of silencing RNA to knock down ERR-gamma restored sensitivity to tamoxifen, they said.
The tamoxifen-resistant cell lines also exhibited increased ERR gamma-driven transcription, which was inhibited by activator protein 1 (AP1) to restore or enhance tamoxifen sensitivity.
"These data support a role for ERR-gamma/AP1 signaling in the development of tamoxifen resistance, and suggest that expression of ERR-gamma may be a marker for poor tamoxifen response," the researchers concluded.
Invasive lobular carcinoma accounts for only about 15% of invasive breast cancer diagnoses annually, but the incidence has increased significantly over the past two decades among postmenopausal women in Western Europe and the United States, the authors said.
In contrast, the incidence of the more common invasive ductal carcinoma has remained stable, they said.
Furthermore, compared with invasive ductal carcinoma, a greater percentage of invasive lobular cancers are receptor positive, suggesting that patients with these cancers should be ideal candidates for endocrine therapy. However, that has not been borne out consistently in clinical trials, the authors said.
Endocrine resistance in invasive lobular breast cancer has been difficult to study because of a lack of appropriate models. Recently, Dr. Riggins and colleagues developed a cell-culture model of endocrine resistance specific to invasive lobular carcinoma. Further studies led to a cell line that is stably resistant to tamoxifen (SUM44/LCCTam).
In a series of experiments, the authors showed that SUM44 control cells entered cell-cycle arrest when exposed to 4-hydroxytamoxifen but SUM44/LCCTam did not.
Subsequently, microarray analysis revealed almost 400 genes with altered expression patterns in SUM44 versus SUM44/LCCTam.
The researchers found that expression of ER-alpha was decreased more than threefold in SUM44 versus SUM44/LCCTam cells and expression of ERR-gamma was increased by more than fourfold by microarray analysis and by 10-fold by quantitative PCR in the tamoxifen-resistant cells versus the SUM44 control cells.
They conducted experiments showing that ERR-gamma expression was decreased by two- to threefold by silencing RNA, leading to partial restoration of tamoxifen sensitivity to the SUM44/LCCTam cells.
They also found that transfection of SUM44 control cells with a murine homolog of ERR-gamma led to tamoxifen resistance.
In contrast, cells remained responsive to the growing-inhibiting effects of tamoxifen when transfected with an empty vector.
The researchers confirmed their findings by repeating studies with another ER-positive, tamoxifen-sensitive cell line thought to be lobular in origin.
In an effort to understand the mechanisms by which ERR-gamma upregulation confers tamoxifen resistance, they examined the ability of 4-HT-bound ERR-gamma to regulate transcription at AP1 sites.
They performed studies showing that inhibition of AP1 restored tamoxifen-mediated growth inhibition in LCCTam cells and enhanced the inhibitory effects in SUM44 control cells.
"Our functional data suggest that in LCCTam cells, increased ERR gamma-driven AP1 transcriptional activity is most strongly associated with tamoxifen resistance," they said.
Finally, the authors searched a database for genes that were upregulated by at least twofold in SUM44/LCCTam cells and also had AP1 response elements in their promoter regions.
The work led them to two genes, HMGCS2 and FASN, whose activities and products have been implicated in the etiology, progression, and hormone sensitivity of breast cancer.
"Therefore we suggest that HMGCS2 and FASN may be two novel ERR-gamma/AP1 targets in tamoxifen resistant breast cancer," the authors concluded.
The research was supported by the Ladies Auxiliary to the Veterans of Foreign Wars, the Susan G. Komen Foundation, the Department of Defense, and the National Cancer Institute.
The authors reported no disclosures.
Primary source: Cancer Research Source reference: Riggins RB et al. "ERR? mediates tamoxifen resistance in noivel models of invasive lobular breast cancer." Cancer Res. 2008;epub.
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