The ratio of
PAX2 to AIB-1 protein expression may be predictive of the effectiveness of
tamoxifen in
breast cancer treatment. Several molecular mechanisms implicate NCOA3 (AIB1) in the
endocrine therapy resistance (depicted in the figure). Signaling pathways or mutations (i.e.
HER2/neu overexpression, activating mutations in
PIK3CA (PI3K), activating mutations in the proto-oncogene tyrosine-protein kinase
Src, etc.) that lead to persistent activation of
ERK and/or
PIK3CA/AKT kinase pathways result, in one hand in an enhanced AIB1 transcriptional coactivation capacity, and in the other hand in the inhibition of the proteasome-dependent AIB1 turn-over and therefore, in AIB1 overexpression. In both conditions, the equilibrium of estrogen receptor (ER) complex formation is displaced towards a transcriptionally active complex and thus, counteracting the inhibition caused by anti-estrogenic drugs such as
tamoxifen or
fulvestrant (
selective estrogen receptor modulators). The result is the restoration of estrogen-sensitive gene transcription and the promotion of cancer progression and/or relapse. Notably, tumors diagnosed with concomitant overexpression of AIB1 and
HER2/neu have worse outcome with tamoxifen therapy than all other patients combined. In addition, dormant tumor cells of luminal breast cancers treated with endocrine therapy may acquire with time, mutations that alter kinase signalling pathways and ultimately enhance AIB1 oncogenic functions. Also, estrogen receptor-PAX2 complexes repress HER2/neu expression, but loss of
PAX2 expression may result in de novo HER2/neu expression and initiate endocrine therapy resistance and relapse. == Interactions ==