Abstract
Basal-like breast cancers (BLBCs) are aggressive breast cancers associated with poor survival. Defining the key drivers of BLBC growth will allow identification of molecules for targeted therapy. In this study, we performed a primary screen integrating multiple assays that compare transcription factor expression and activity in BLBC and non-BLBC at the RNA, DNA, and protein levels. This integrated screen identified 33 transcription factors that were elevated in BLBC in multiple assays comparing mRNA expression, DNA cis-element sequences, or protein DNA-binding activity. In a secondary screen to identify transcription factors critical for BLBC cell growth, 8 of the 33 candidate transcription factors (TFs) were found to be necessary for growth in at least two of three BLBC cell lines. Of these 8 transcription factors, SOX11 was the only transcription factor required for BLBC growth, but not for growth of non-BLBC cells. Our studies demonstrate that SOX11 is a critical regulator of multiple BLBC phenotypes, including growth, migration, invasion, and expression of signature BLBC genes. High SOX11 expression was also found to be an independent prognostic indicator of poor survival in women with breast cancer. These results identify SOX11 as a potential target for the treatment of BLBC, the most aggressive form of breast cancer.
Highlights
Breast cancer is a heterogeneous disease that can be divided into clinically defined subtypes including estrogen receptor (ER)-positive, HER2-positive, and triple-negative breast cancer (TNBC, which lack ER, progesterone receptor (PR) and HER2), or molecularly defined subtypes including luminal A, luminal B, HER2-enriched and basal-like breast cancer (BLBC)
We used DNA sequences from promoters of genes highly expressed in BLBC to identify transcription factor motifs that are overrepresented in BLBC gene promoters
We focused on transcription factors which were critical for growth in BLBC cell lines and identified 8 transcription factors that were critical for the growth of BLBC
Summary
Breast cancer is a heterogeneous disease that can be divided into clinically defined subtypes including estrogen receptor (ER)-positive, HER2-positive, and triple-negative breast cancer (TNBC, which lack ER, progesterone receptor (PR) and HER2), or molecularly defined subtypes including luminal A, luminal B, HER2-enriched and basal-like breast cancer (BLBC). Identifying critical regulators specific to these subtypes has led to the development of targeted therapies; endocrine therapy for ER-positive breast cancer patients [1], and HER2-targeting therapies for patients with HER2-amplified tumors [2]. As TNBCs lack ER, PR, and HER2, they do not respond to these available targeted therapies. Key regulators of TNBC tumor growth have not been defined. Of TNBC can be molecularly defined as BLBC by mRNA expression [3]. To develop effective targeted therapies for this aggressive type of breast cancer, a better understanding of the key regulators of BLBC is required
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