Researchers Describe Aggressive Breast Cancer Molecular Mechanism

Cancer researchers have found that SIRT2, a member of the sirtuin family of enzymes, stabilizes Slug, a transcription factor that promotes the development, growth, and spread of basal-like breast cancer.

Overabundance of Slug protein is common in human cancer and represents an important determinant underlying the aggressiveness of basal-like breast cancer (BLBC). Despite its importance, this transcription factor is rarely mutated in BLBC, and the mechanism of its deregulation in cancer remains unknown.

To better understand the link between Slug and BLBC, investigators at Tufts University School of Medicine (Boston, MA, USA) screened BLBC cultures for factors that would stabilize Slug activity.

They reported in the October 25, 2016, online edition of the journal Cell Reports that Slug underwent acetylation-dependent protein degradation and identified the deacetylase SIRT2 as a key mediator of this post-translational mechanism. SIRT2 inhibition rapidly destabilized Slug, whereas SIRT2 overexpression extended Slug stability. SIRT2 deacetylated Slug protein at lysine residue K116 to prevent Slug degradation.

SIRT2 was frequently amplified and highly expressed in BLBC. Genetic depletion and pharmacological inactivation of SIRT2 in BLBC cells reversed Slug stabilization, caused the loss of clinically relevant pathological features of BLBC, and inhibited tumor growth. Without SIRT2, tumor cells had a more than 60% reduction in invasive capacity compared to normal basal-like tumor cells. SIRT2-depleted cells also had significantly decreased capacity for growth and self-renewal. This diminished malignancy could be reversed by artificially introducing Slug protein back into cells.

"Breast cancer is not one disease, and of the several distinct subtypes, basal-like breast cancer represents the most aggressive form. By targeting a master transcription factor regulator in basal-like cells, we were able to reduce malignant behaviors," said senior author Dr. Charlotte Kuperwasser, professor of developmental, molecular, and chemical biology at Tufts University School of Medicine. "Our findings now provide a molecular rationale for new approaches to help improve the poor clinical outcomes currently associated with these cancers."

"Cancer cells find sophisticated ways to regulate essential proteins they need for their survival and growth. The transcriptional factor Slug is one such protein and is often tightly regulated in both normal and cancer cells. While we have found that SIRT2 plays an important role in prolonging Slug expression, it is too soon to know whether targeting SIRT2 will be sufficient to abolish Slug entirely in cancer cells and therefore lead to tumor regression," said Dr. Kuperwasser. "A significant amount of work remains to be done before we can verify if targeting SIRT2 can be an Achilles' heel for treating basal-like breast cancers."

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Tufts University School of Medicine