Mediator of DNA Damage Checkpoint 1 (MDC1) is a Novel Estrogen Receptor Coregulator in invasive Lobular Carcinoma of the Breast

Abstract

Invasive lobular carcinoma (ILC) is the most common special ation and tamoxifen resistance. Using RNA-sequencing, we found histologic subtype of breast cancer, and nearly all ILC tumors in ILC cells MDC1 knockdown broadly dysregulates the ER tranexpress estrogen receptor alpha (ER). However, clinical and laboscriptome, with ER:MDC1 target genes enriched for promoter ratory data suggest ILC are strongly estrogen-driven but not equally hormone response elements. Importantly, our data are inconsistent antiestrogen-sensitive. We hypothesized ILC-specific ER coregulawith MDC1 tumor suppressor functions in DDR, but suggest a tors mediate ER functions and antiestrogen resistance in ILC, and novel oncogenic role for MDC1 as an ER coregulator. Supporting profiled ER-associated proteins by mass spectrometry. Three ERþ this, in breast tumor tissue microarrays, MDC1 protein was freILC cell lines (MDA MB 134VI, SUM44PE, and BCK4) were quently low or absent in IDC, but MDC1 loss was rare in ERþ ILC. compared with ERþ invasive ductal carcinoma (IDC) line data, ER:MDC1 interaction and MDC1 coregulator functions may and we examined whether siRNA of identified proteins suppressed underlie ER function in ILC and serve as targets to overcome ER-driven proliferation in ILC cells. This identified mediator of antiestrogen resistance in ILC. DNA damage checkpoint 1 (MDC1), a tumor suppressor in DNA damage response (DDR), as a novel ER coregulator in ILC. We Implications: MDC1 has novel ER coregulator activity in ILC, confirmed ER:MDC1 interaction was specific to ILC versus IDC which may underlie ILC-specific ER functions, estrogen response, cells, and found MDC1 knockdown suppressed ILC cell prolifer- and antiestrogen resistance.