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Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion.

Publication ,  Journal Article
Elsarraj, HS; Hong, Y; Valdez, KE; Michaels, W; Hook, M; Smith, WP; Chien, J; Herschkowitz, JI; Troester, MA; Beck, M; Inciardi, M; May, L ...
Published in: Breast Cancer Res
September 17, 2015

INTRODUCTION: There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of patients. We profiled the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using in vivo DCIS progression models. These studies identified B cell lymphoma-9 (BCL9) as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated β-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However BCL9 role in breast cancer had not been previously recognized. METHODS: Microarray and RNA sequencing were utilized to characterize the sequential changes in mRNA expression during DCIS invasive transition. BCL9-shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, epithelial-mesenchymal transition (EMT) and canonical Wnt-signaling. Immunofluorescence of 28 patient samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers. RESULTS: Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2). In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of EMT. Analysis of the TCGA data showed BCL9 to be altered in 26 % of breast cancers. This is a significant alteration when compared to HER2 (ERBB2) gene (19 %) and estrogen receptor (ESR1) gene (8 %). A significantly higher proportion of basal like invasive breast cancers compared to luminal breast cancers showed BCL9 amplification. CONCLUSION: BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC.

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Published In

Breast Cancer Res

DOI

EISSN

1465-542X

Publication Date

September 17, 2015

Volume

17

Start / End Page

128

Location

England

Related Subject Headings

  • beta Catenin
  • Wnt Proteins
  • Up-Regulation
  • Transcriptome
  • Transcription, Genetic
  • Transcription Factors
  • Receptors, Progesterone
  • Receptors, Estrogen
  • Receptor, erbB-2
  • Receptor, ErbB-2
 

Citation

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Elsarraj, H. S., Hong, Y., Valdez, K. E., Michaels, W., Hook, M., Smith, W. P., … Behbod, F. (2015). Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion. Breast Cancer Res, 17, 128. https://doi.org/10.1186/s13058-015-0630-z
Elsarraj, Hanan S., Yan Hong, Kelli E. Valdez, Whitney Michaels, Marcus Hook, William P. Smith, Jeremy Chien, et al. “Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion.Breast Cancer Res 17 (September 17, 2015): 128. https://doi.org/10.1186/s13058-015-0630-z.
Elsarraj HS, Hong Y, Valdez KE, Michaels W, Hook M, Smith WP, et al. Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion. Breast Cancer Res. 2015 Sep 17;17:128.
Elsarraj, Hanan S., et al. “Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion.Breast Cancer Res, vol. 17, Sept. 2015, p. 128. Pubmed, doi:10.1186/s13058-015-0630-z.
Elsarraj HS, Hong Y, Valdez KE, Michaels W, Hook M, Smith WP, Chien J, Herschkowitz JI, Troester MA, Beck M, Inciardi M, Gatewood J, May L, Cusick T, McGinness M, Ricci L, Fan F, Tawfik O, Marks JR, Knapp JR, Yeh H-W, Thomas P, Carrasco DR, Fields TA, Godwin AK, Behbod F. Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion. Breast Cancer Res. 2015 Sep 17;17:128.

Published In

Breast Cancer Res

DOI

EISSN

1465-542X

Publication Date

September 17, 2015

Volume

17

Start / End Page

128

Location

England

Related Subject Headings

  • beta Catenin
  • Wnt Proteins
  • Up-Regulation
  • Transcriptome
  • Transcription, Genetic
  • Transcription Factors
  • Receptors, Progesterone
  • Receptors, Estrogen
  • Receptor, erbB-2
  • Receptor, ErbB-2