Abstract
Most breast cancers are estrogen receptor-positive and treated with antiestrogens, but aberrant signaling networks can induce drug resistance. One of these networks involves the scaffolding protein BCAR1/p130CAS, which regulates cell growth and migration/invasion. A less investigated scaffolding protein that also confers antiestrogen resistance is the SH2 domain-containing protein BCAR3. BCAR1 and BCAR3 bind tightly to each other through their C-terminal domains, thus potentially connecting their associated signaling networks. However, recent studies using BCAR1 and BCAR3 interaction mutants concluded that association between the two proteins is not critical for many of their interrelated activities regulating breast cancer malignancy. We report that these previously used BCAR mutations fail to cause adequate loss-of-function of the complex. By using structure-based BCAR1 and BCAR3 mutants that lack the ability to interact, we show that BCAR3-induced antiestrogen resistance in MCF7 breast cancer cells critically depends on its ability to bind BCAR1. Interaction with BCAR3 increases the levels of phosphorylated BCAR1, ultimately potentiating BCAR1-dependent antiestrogen resistance. Furthermore, antiestrogen resistance in cells overexpressing BCAR1/BCAR3 correlates with increased ERK1/2 activity. Inhibiting ERK1/2 through overexpression of the regulatory protein PEA15 negates the resistance, revealing a key role for ERK1/2 in BCAR1/BCAR3-induced antiestrogen resistance. Reverse-phase protein array data show that PEA15 levels in invasive breast cancers correlate with patient survival, suggesting that PEA15 can override ERK1/2 activation by BCAR1/BCAR3 and other upstream regulators. We further uncovered that the BCAR3-related NSP3 can also promote antiestrogen resistance. Thus, strategies to disrupt BCAR1-BCAR3/NSP3 complexes and associated signaling networks could ultimately lead to new breast cancer therapies.
Highlights
BCAR1 and BCAR3 promote antiestrogen resistance and malignancy in breast cancer
The BCAR3-related NSP3 Can Promote Morphological Changes and Antiestrogen Resistance—Besides BCAR3, we examined the effects of the novel SH2-containing protein (NSP) family member NSP3, which is expressed in breast cancer cells albeit at lower levels than BCAR3 [23]
NSP family proteins have emerged as critical regulators of BCAR1 and other members of the CAS family under physiological as well as pathological conditions [11, 12]
Summary
BCAR1 (breast cancer antiestrogen resistance protein 1) and BCAR3 promote antiestrogen resistance and malignancy in breast cancer. The tight linkage formed by their C-terminal domains allows members of the BCAR1 and NSP families to connect the signaling networks associated with each multidomain scaffolding protein This is in line with earlier suggestions that the level of the BCAR1-BCAR3 complex in breast cancer cell lines correlates with malignancy more closely than the levels of each individual protein [23]. Recent studies of mutations in the C-terminal interaction domains of mouse BCAR1 (L791P) and BCAR3 (R743A) have shown that the mutants retain many biological activities of the wild-type proteins despite their reported decreased ability to interact [30, 38, 39] These findings have cast doubt on the importance of the BCAR1-BCAR3 association for many of their interrelated biological functions regulating breast cancer aggressiveness. Knowing whether the physical association between BCAR1 and BCAR3 represents a key factor in breast cancer malignancy and drug resistance as well as characterizing the signaling events involved has important implications for breast cancer prognosis and therapy
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