Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype

Abstract

Steroid regulated cancer cells use nuclear receptors and associated regulatory proteins to orchestrate transcriptional networks to drive disease progression. In primary breast cancer, the coactivator AIB1 promotes estrogen receptor (ER) transcriptional activity to enhance cell proliferation. The function of the coactivator in ER+ metastasis however is not established. Here we describe AIB1 as a survival factor, regulator of pro-metastatic transcriptional pathways and a promising actionable target. Genomic alterations and functional expression of AIB1 associated with reduced disease-free survival in patients and enhanced metastatic capacity in novel CDX and PDX ex-vivo models of ER+ metastatic disease. Comparative analysis of the AIB1 interactome with complementary RNAseq characterized AIB1 as a transcriptional repressor. Specifically, we report that AIB1 interacts with MTA2 to form a repressive complex, inhibiting CDH1 (encoding E-cadherin) to promote EMT and drive progression. We further report that pharmacological and genetic inhibition of AIB1 demonstrates significant anti-proliferative activity in patient-derived models establishing AIB1 as a viable strategy to target endocrine resistant metastasis. This work defines a novel role for AIB1 in the regulation of EMT through transcriptional repression in advanced cancer cells with a considerable implication for prognosis and therapeutic interventions.

Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities

“…To understand the biological significance of this we further tested the functionality of the HRD in luminal BCBM using patient-derived tumor explants (PDTEs) 27 and patient-derived organoid cultures (Supplementary Data 20 ). PDTEs were established from brain metastatic tissue from 3 breast cancer patients: T347 (ER + /HER2 − primary breast to ER + /HER2 amplified in BCBM), T638 (ER + /HER2 − primary breast tumor to ER + ; gained HER2 expression in BCBM, HER2 non-amplified), T328 (ER + /HER2 − in both primary breast and brain metastatic tumors) and from independent pleural/lung metastatic material in 2 of the samples HCI05 (ER + /HER2 + ) and HCI-011 (ER + /HER2 − ), all expanded in the mammary fat pad.…”

“…HCI05 and HCI-011 models were a kind gift from Alana Welm lab 67 . Patient-derived tumor explant (PDTEs) of luminal brain metastasis (T347, T638 and T328) were established by culturing 2–4 mm 3 biobanked tumor fragments on hemostatic gelatin dental sponges (Vetspon, Novartis) pre-soaked with human mammary epithelial media as described previously 27 . The PDTEs were treated with Niraparib or DMSO for 72 h after which they were paraffin-embedded and profiled with immunohistochemistry (IHC).…”

SRC-3, a Steroid Receptor Coactivator: Implication in Cancer

“…As a coactivator, SRC-3 also up-regulated MMP7 and MMP10 by mediating AP-1 activity to promote invasiveness [ 107 ]. According to comparative analysis of SRC-3 interactome, a recent study has shown that SRC-3 served as a transcriptional repressor by interacting with the chromatin remodeling factor MTA2, which inhibited the expression of E-cadherin to promote EMT and pro-metastatic phenotype in ER positive breast cancer [ 108 ]. SRC-3 also was required to maintain myoepithelial progenitor cells in ductal carcinoma in situ (DCIS) lesion via NOTCH and HER-2/HER-3 signaling molecules, thus increasing incidence of invasive breast cancer [ 109 ].…”

Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies

“…SRC-3 can lead to tamoxifen resistance via promoting the expression of ER target genes [41], and other oncogenic proteins, such as HER2 [42] in the presence of tamoxifen. Furthermore, it was shown to inhibit the transcription of E-cadherin and promote ER + breast cancer metastasis [43]. SRC-3 was identified as a novel binding partner of proline, glutamic acid, leucine-rich protein 1 (PELP1), which is overexpressed in approximately 80% of invasive breast tumors.…”