Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast.

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