Invasive
lobular carcinoma (ILC) is the most common special histologic 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
antiestrogen-sensitive. We hypothesized ILC-specific ER coregulators mediate ER functions and
antiestrogen resistance in ILC, and profiled ER-associated
proteins by mass spectrometry. Three ER+ ILC cell lines (MDA MB 134VI, SUM44PE, and BCK4) were compared with 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 coregulator 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 coregulator. 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 coregulator functions may underlie ER function in ILC and serve as targets to overcome
antiestrogen resistance in ILC. IMPLICATIONS: MDC1 has novel ER coregulator activity in ILC, which may underlie ILC-specific ER functions,
estrogen response, and
antiestrogen resistance.