The chromatin remodeler SMARCD3 regulates cell cycle progression and its expression predicts survival outcome in ER+ breast cancer

Abstract

Chromatin remodeling plays an essential role in regulating transcriptional networks and timing of gene expression. Chromatin remodelers such as SWItch/Sucrose Non-Fermentable (SWI/SNF) harbor many protein components, with the catalytic subunit providing ATPase activity to displace histones along or from the DNA molecules, and associated subunits ensuring tissue specificity and transcriptional or cotranscriptional activities. Mutations in several of the SWI/SNF subunits have been linked to cancer. Here, we describe how SMARCD3/Baf60c expression is associated with hormone positive (ER+) breast cancer. The level SMARCD3, as detected by immunohistochemistry in breast cancer patient samples, is correlated with differential long-term disease-free survival. In contrast, the expression level of SMARCD1/Baf60a and SMARCD2/Baf60b, which are mutually exclusive within the SWI/SNF complex and have a partially redundant function, lacks predictive value in breast cancer patient samples. Lower proliferation rates are observed in SMARCD3 depleted cells, which reflects a failure to fully progress through G2/M, and an increase in endoreplication. In the absence of SMARCD3, p21 accumulates in cells but does not halt the cell cycle, and DNA damage accumulates and remains unrepaired. Taken together, our data begin to explain why ER+ breast cancer patients with low SMARCD3 expressing tumors exhibit reduced survival rates compared to patients expressing normal or higher levels of SMARCD3. SMARCD3 might act as a tumor suppressor role through regulation of cell cycle checkpoints and could be a reliable and specific breast cancer prognostic biomarker. SignificanceMutations in chromatin remodelers are a leading cause of cancer. Estrogen Receptor positive (ER+) breast cancers represent approximately 80% of all cases diagnosed. Although these tumors can be treated with hormone therapy, most breast cancer fatalities occur in ER+ breast cancer patients, due to metastasis. Low expression of SMARCD3 in ER+ cancer is associated with diminished survival rates. As such, SMARCD3 could be used as a predictive biomarker for survival. In addition, we have identified a role for SMARCD3 in the cell cycle, which could at least partially explain its protective role in breast cancer. While catalytic subunits are often viewed as the major components in chromatin remodeling function, we show here new evidence that mutations or silencing of SMARCD3 may also contribute to genomic instability and thus development of breast cancer.

SMARCD3 Overexpression Promotes Epithelial–Mesenchymal Transition in Gastric Cancer

“…SMARCD3, also known as BAF60C, is a member of the SWI/SNF chromatin remodeling complex and has been implicated in various cancers, exerting diverse roles depending on the specific cancer type [ 27 , 28 , 29 , 30 ]. In pancreatic cancer, SMARCD3 has been associated with a poor prognosis.…”

“…Mechanistically, SMARCD3 has been linked to promoting tumor growth and invasion in pancreatic cancer cells. Conversely, in uterine and breast cancers, SMARCD3 acts as a tumor suppressor [ 28 , 30 , 34 ]. Studies have shown that loss of SMARCD3 expression is associated with aggressive tumor behavior, increased metastasis, and poorer patient outcomes.…”

“…The role of SMARCD3 differs across cancer types. In pancreatic cancer, SMARCD3 is linked to a poor prognosis [ 29 ], while in uterine and breast cancers, it functions as a tumor suppressor [ 30 ]. However, its role in gastric cancer has not been thoroughly investigated.…”