Scientists at Sanford-Burnham Medical Research Institute (Sanford-Burnham) provide compelling and conclusive evidence that antiestrogen resistance in breast cancer cells requires the interaction between proteins called BCAR1 and BCAR3. In the study, published in the Journal of Biological Chemistry, the researchers also identified a signaling pathway that is crucial for drug resistance mediated by this protein complex.
"Drug resistance is one of the most serious obstacles to breast cancer eradication," said senior study author Elena Pasquale, Ph.D., professor in the National Cancer Institute-designated Cancer Center and the Tumor Initiation and Maintenance Program at Sanford-Burnham. "Our findings suggest that strategies to disrupt the BCAR1-BCAR3 complex and associated signaling networks could potentially overcome this obstacle and ultimately lead to more-effective breast cancer therapies."
Breast cancer is the most common cancer in women in the United States, and despite advances in treatment strategies, about 10 percent of these patients die within five years of being diagnosed. One major factor contributing to these deaths is the development of intrinsic or acquired resistance to antiestrogen drugs, which interfere with the ability of the hormone estrogen to stimulate the growth of breast cancer cells. Two proteins implicated in antiestrogen resistance and malignancy are breast cancer antiestrogen resistance proteins 1 and 3 (BCAR1 and BCAR3), which can bind together to potentially connect the signaling pathways they each regulate. Indeed, the levels of BCAR1-BCAR3 complexes are more closely associated with malignancy compared with the levels of each individual protein. But a few studies have cast doubt on the importance of the BCAR1-BCAR3 complex in regulating breast cancer aggressiveness.
A few years ago, when a group of researchers generated a mutation in an amino acid that mediates binding between BCAR1 and BCAR3, the breast cancer cells still exhibited antiestrogen resistance, suggesting that the BCAR1-BCAR3 complex is not required for drug resistance.
However, Pasquale and her team subsequently found that single amino acid mutations at BCAR1-BCAR3 binding sites may not be sufficient to adequately disrupt the formation of the protein complex, possibly because two separate binding sites work together to generate a very strong interaction between these proteins. "Based on our data, we suspected that the BCAR mutations used in previous studies did not sufficiently block the formation of the BCAR1-BCAR3 complex and disrupt downstream signaling pathways, leaving the role of this protein complex in drug resistance an open question," Pasquale said.
To unambiguously answer this question in the new study, Pasquale and her team collaborator Stefan Riedl, Ph.D., associate professor in Sanford-Burnham's NCI-designated Cancer Center, generated mutations in two amino acids of BCAR3 to effectively disrupt the interaction between the two proteins. Consistent with previous findings, a single amino acid mutation in BCAR3 did not prevent the protein from interacting with BCAR1 and did not interfere with the growth of breast cancer cells treated with an antiestrogen drug. By contrast, this drug inhibited the growth of breast cancer cells expressing the double mutant BCAR3, suggesting that the BCAR1-BCAR3 complex is required for antiestrogen resistance.
The researchers also found that antiestrogen resistance mediated by the BCAR1-BCAR3 complex depends on ERK1/2 signaling, which was previously implicated in breast cancer malignancy. ERK1/2 stands for extracellular-signal-regulated kinase 1 and 2, and carries out activation and signaling tasks between molecules and cells. Moreover, analysis of more than 400 tumors from an invasive breast cancer study revealed that higher levels of an ERK1/2-inhibiting protein called PEA15 were predictive of longer patient survival.
On the other hand, the antiestrogen drug did not stymie the growth of breast cancer cells that were genetically modified to express high levels of a BCAR3-related protein called NSP3, suggesting that this protein also promotes drug resistance. "Taken together, our findings suggest that NSP3 and PEA15 protein levels could represent useful new prognostic indicators, in conjunction with BCAR1-BCAR3 and ERK1/2 signaling," Pasquale said.
In addition to improving diagnostic approaches, the findings could have important implications for treatment strategies. "The fact that the BCAR1-BCAR3 interaction is remarkably tight and modifications that substantially weaken it are not sufficient to impair many of the functional effects of the protein complex suggests that inhibiting downstream signaling pathways may be a more viable therapeutic approach," Pasquale said. "In particular, inhibiting ERK1/2 activity through PEA15 may be a useful strategy to counteract breast cancer malignancy and resistance to chemotherapeutic agents."
- Y. Wallez, S. J. Riedl, E. B. Pasquale. Association of the Breast Cancer Antiestrogen Resistance Protein 1 (BCAR1) and BCAR3 Scaffolding Proteins in Cell Signaling and Antiestrogen Resistance. Journal of Biological Chemistry, 2014; 289 (15): 10431 DOI: 10.1074/jbc.M113.541839
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