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Researchers Uncover Mechanism Behind Tamoxifen-Resistant Breast Cancer

NEW YORK (GenomeWeb News) – New research suggests that resistance to the breast cancer drug tamoxifen may be linked to both estrogen receptor and ERBB2/HER-2 pathways.
 
In a paper appearing online today in Nature, researchers from the UK and the US used genome-wide ChIP-chip to help uncover factors contributing to tamoxifen resistance in estrogen receptor-positive breast cancer. Their results suggest that cells can acquire resistance to tamoxifen by either amplifying or de-regulating the ERBB2/HER-2 gene, which is repressed by a factor called PAX2 and de-repressed by the ER co-activator AIB-1. AIB-1 seems to contribute to drug resistance by out-competing PAX2.
 
“The repression of ERBB2 by ER-PAX2 links these two breast cancer subtypes and suggests that aggressive ERBB2-positive tumors can originate from ER-positive luminal tumors by circumventing this repressive mechanism,” senior author Jason Carroll, a cancer researcher at the Cancer Research UK Cambridge Research Institute, and his colleagues wrote. “These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer.”
 
Tamoxifen is among the most effective breast cancer treatments. It acts by interfering with the action of the hormone estrogen in breast tissue. That stifles the growth of estrogen receptor positive or ER-positive breast cancer tumors, which rely on estrogen to grow.
 
Although the drug has been quite successful, tamoxifen resistance is a common problem. This resistance has been previously linked with higher than normal levels of ERBB2 or over-expression of genes involved in the ERBB2/HER-2 pathway, though the mechanism has not been well-characterized.
 
For the latest paper, Carroll and his team first used an Affymetrix seven GeneChip tiling array 2.0R set to do genome-wide estrogen receptor chromatin immunoprecipitation (ChIP)-on-chip analyses of ER-positive MCF-7 cells. Using this approach, the team found 8,525 estrogen receptor binding sites — including a binding site in the ERBB2/HER-2 region of the genome.
 
The researchers found that these ER-binding sites were also statistically enriched for the paired box 2 gene or PAX2 transcription factor motif. Although its function is poorly understood, PAX2 is expressed in some breast cancers and also seems to act as a tamoxifen-regulated effector in endometrial cells.
 
In most cases, the researchers found that PAX2 was recruited to ER-binding sites only after tamoxifen treatment. But there was one exception: PAX2 was recruited to ER-binding sites in ERBB2/HER-2 after either tamoxifen or estrogen treatment, suggesting PAX2 may act as what the researchers described as a “general ER-associated transcriptional repressor.”
 
Based on these and other experiments, the team proposed that the ERBB2 ER-binding site might act as a cis-regulatory element, repressing ERBB2 in response to estrogen or tamoxifen. When the team knocked down PAX2 with short interfering RNA, the estrogen- or tamoxifen-induced repression of ERBB2 disappeared.
 
The apparent transcriptional repression by PAX2 was surprising, the team noted, given previous research implicating PAX2 as a transcriptional activator. The researchers suggested that such contradictions may reflect tissue-specific differences in PAX2 effects. And, they noted, these differences may contribute to tissue-specific tamoxifen effects.
 
And because ER-positive tumors with elevated ERBB2 levels also tend to be those with the poorest prognosis, Carroll and his team reasoned that tamoxifen resistance may reflect this interconnection between the ER and ERBB2 pathways.
 
In contrast, higher levels of the ER co-activator AIB-1 increased ERBB2 expression. The researchers found that PAX and AIB-1 compete for ERBB2 binding, with high-levels of AIB-1 reversing the PAX2-mediated repression of ERBB2 following estrogen or tamoxifen treatment. That, in turn, helps to explain previous observations that AIB-1 decreases tamoxifen responsiveness in ER-positive breast cancer cells.
 
“We therefore proposed that the anti-proliferative effects of tamoxifen treatment require repression of ERBB2, and that breast cancers can potentially acquire tamoxifen resistance by amplifying the ERBB2 locus or by deregulating the control mechanisms that normally repress ERBB2 transcription,” Carroll and his team explained.
 
Indeed, when the team looked at PAX2 levels in 109 ER-positive breast cancer samples they found a correlation between the 68 PAX2-positive tumors and improved recurrence-free survival. Even so, those with both PAX2-positive and AIB-1-positive tumors tended to have worse clinical outcomes than those with AIB-1-negative tumors.
 
Overall, the research provides new insights into the biology behind both tamoxifen-resistance and the interconnectedness of breast cancer-related pathways.
 
“We now provide evidence that PAX2 is a critical tamoxifen-recruited transcriptional repressor of the ERBB2 gene and that increased AIB-1 expression can out-compete PAX2 binding, directly resulting in increased ERBB2 expression,” the authors wrote. “These data suggest an intrinsic transcriptional link between tumors driven by ER and those driven by ERBB2, which together account for a significant majority of all breast cancers.”

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