Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters.
Using this strategy, we have isolated three novel amplified genes (termed AIB1, AIB3, and AIB4) from a cDNA library constructed from the 20q amplified breast cancer cell line BT-474.
Furthermore, <i>in vivo</i> syngeneic tumor studies revealed that PELP1 knockdown resulted in increased survival of tumor-bearing mice as compared with mice injected with control cells.<b>Implications:</b> These data demonstrate that cytoplasmic PELP1/AIB1-containing complexes function to promote advanced cancer phenotypes, including outgrowth of stem-like cells, associated with estrogen-independent breast cancer progression.<i></i>.
This study establishes a role for AIB1 in AI-resistant breast cancer and describes a new mechanism of ERα/AIB1 gene regulation which could contribute to the development of an aggressive tumor phenotype.
We recently demonstrated that the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger (POZ) domain protein (SPOP) interacts directly with SRC-3 and promotes its cullin 3-dependent ubiquitination and proteolysis in breast cancer, thus functioning as a potential tumor suppressor.
Collectively, these data indicate that SRC control of basal and hormone-regulated proliferations is not solely mediated by ERα, and suggest that targeting growth inhibition by disrupting SRC-2 and SRC-3 function may be an effective approach to inhibit the growth of tamoxifen-resistant breast cancer.
AIB1 was analyzed with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group's trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs).
AIB1, a member of the steroid receptor co-activator-1 family, has been cloned on 20q12 as a candidate target gene for this amplification in human breast cancers.
Thus, our results reveal an essential role of ACTR in control of breast cancer cell proliferation and implicate the ACTR-E2F1 pathway as a novel mechanism in antiestrogen resistance.
The SNP and CGH array both detected cytogenetic abnormalities commonly found in breast cancer: amplification of chromosomes 11q13-14.1, 17q and 20q containing cyclin D1, BCAS1 and 3 (Breast Cancer Amplified Sequence) and AIB1 (Amplified in Breast cancer) genes; losses at 6q, 9p and X chromosomes, which included ERalpha (Estrogen Receptor alpha) and p16 ( INK4A ) genes.
The transcriptional coactivator Amplified in Breast Cancer 1 (AIB1) plays a major role in the progression of hormone and HER2-dependent breast cancers but its role in triple negative breast cancer (TNBC) is undefined.
Thus, we set out to identify novel single nucleotide polymorphisms (SNPs) within SRC-1 (NCoA1), SRC-3 (NCoA3, AIB1), NCoR (NCoR1), and SMRT (NCoR2), and test the most promising SNPs for associations with breast cancer risk.
Amplified in breast cancer 1 (AIB1) is a candidate oncogene in human breast cancer, which has been identified to be amplified and overexpressed in several types of other human cancers.
In addition to finding previously well-known drivers, the identified modules pointed to other novel findings such as the interaction between NCOR2 and NCOA3 in breast cancer.
To determine the role of AIB1-Delta3 in breast cancer pathogenesis, we generated transgenic mice with human cytomegalovirus immediate early gene 1 (hCMVIE1) promoter-driven over-expression of human AIB1/ACTR-Delta3 (CMVAIB1/ACTR-Delta3 mice).
Subsequent evaluation of 105 unselected specimens of primary breast cancer found AIB1 amplification in approximately 10 percent and high expression in 64 percent of the primary tumors analyzed.
This review summarizes the possible mechanisms of how dysregulation of AIB1 at multiple levels can lead to the initiation and progression of breast cancer as well as its role as a predictor of response to breast cancer therapy, and as a possible therapeutic target.
The ability of ER-alpha, but not ER-beta to recruit SRC-3 in the presence of tamoxifen may in part explain the differential ER isoform associations with recurrence in human breast cancer.