E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

Abstract

Coactivator activator (CoAA) is a dual-functional coregulator that regulates steroid receptor-mediated transcription and alternative splicing. Previously, we have shown that CoAA has tumor-suppressive potential in tumorigenic human kidney cells. Here, we uncover a molecular mechanism by which Sjogren syndrome-associated autoantigen (SSA), an estrogen receptor (ER) coactivator, induces MYC oncogene by removing repressive CoAA through E2-dependent degradation of CoAA and promotes G 1 /S transition of the cell cycle as well as anchorage-independent growth capability of breast cancer cells. We also show that E2 and ER enhance the E3 ligase activity of SSA to modulate CoAA through splicing isoform-selective ubiquitylation. We propose this as one potential molecular basis for the reduced tumor incidence in autoimmune disease patients and suggest SSA as a potential therapeutic target to treat breast cancer.

Mastitis in Autoimmune Diseases: Review of the Literature, Diagnostic Pathway, and Pathophysiological Key Players

“…The anatomical, histological, and physiological roles of salivary glands and mammary glands are similar as they both belong to the effector sites of the associated mucosal immune system. Their ductal cells share common receptors such as the SSa antigen [35]. This explains why autoimmune diseases such as SjS might target these two glands concomitantly and this is perfectly in line with the literature which considers Sjögren's syndrome as "autoimmune epithelitis" [36,37].…”

“…Thirdly, epithelial breast cells share certain self-antigens involved in autoimmune diseases with other epithelial cells from other targeted tissues. For example, the SSa antigen in SjS is exposed both in salivary and mammary epithelial cells [35,197]. At least, mammary duct self-antigens may exhibit a cross-reactivity towards other autoantibodies.…”

Sjögren syndrome diagnosis in a cohort of patients with breast cancer: a single-center experience

“…36 Nevertheless SSA is an estrogen receptor coactivator that induces MYC oncogene, promotes G(1)/S transition of the cell cycle and growth capability of breast cancer cells. 37 Other hypothesis consider estrogens to protect secretory glandular acinar cells against apoptosis, whereas lack of estrogens specifically leads to increased apoptosis of the exocrine secretory cells. 38,39 In conclusion, data published in the literature, together with our results, indicate a link between BC and SjS.…”

Breast cancer anti-hormonal therapy and rheumatic diseases: linking the clinical to molecular world

“…The observations of a lower incidence of breast cancer in SS or SLE patients and the likely inhibition of E3 ligase activity of SSA by auto-antibodies against SSA in these patients have led to speculate that there is also an oncogenic role for SSA/TRIM 21 in breast cancer. 61 Interestingly, SSA/Trim 21 dysregulation contributes to the progression of autoimmune diseases, but also of different human malignancies. In breast cancer TRIM21 serves as a potential prognostic and therapeutic biomarker 62 and functions as a tumour suppressor.…”

“…In recent times, the association between autoimmune rheumatic diseases and breast cancer therapy has become evident, [1][2][3] but the molecular mechanisms at the basis of this relationship are still being debated. [4][5][6] Our understanding of how cancer therapy can lead to rheumatic autoimmune disease may provide a very important contribution to the elucidation of the autoimmunity "puzzle" and, on the other side, of cancer therapeutic resistance, which can occur through many different mechanism, including the host immune response in which the cancer cell resides. 7,8 Until now, underlying common intercellular interactions and in-terplaying biochemical pathways have had been accompanied by minimal experimental supporting data, [9][10][11] but clinical experience show that this coincidence brings up an interesting observation point.…”