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Author Notes:

Veena N Rao, Professor and Co-Director Cancer Biology Program, GCC Distinguished Cancer Scholar, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Rm 10C011, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, Georgia 30303-3031, USA, Tel: 404-489-9993, Fax: 404-489-9220, vrao@msm.edu

We thank all the members of Drs. Rao and Reddy labs for their help. We thank RCMI core facilities at Morehouse School of Medicine, for their assistance.

Authors have no conflict of interest to disclose.

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Research Funding:

This work was supported in part by Georgia Cancer Coalition Distinguished Cancer Scholar award, NIH-NCRR-RCMI grant G-12-RR003034, U54 RR02613, 5P20RR11104 and NIHMD research endowment grant 2S21MD000101, U54 CA118638 and It’s the Journey Inc. Georgia 2-Day walk for breast cancer and Georgia core to V.N.R. V.N.R’s lab was also supported in part by private funds from the VOYA foundation.

Keywords:

  • BAT
  • BRCA1
  • Collagen
  • ER-α, β-Catenin
  • Fibronectin
  • Mammographic density
  • SIRT1
  • TNBC
  • Ubc9
  • WAT

A Provocative Molecular Link between Mammographic Density and BRCA1-loss associated TNBC.

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Journal Title:

Int J Hum Genet Genet Disord

Volume:

Volume 1, Number 1

Publisher:

, Pages 1-8

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that has a high mortality rate and disproportionately affects young African American (AA) women who carry mutations in the BRCA1 gene. Approximately 80% of breast cancers which develop in BRCA1-mutant carriers will have TNBC and the molecular mechanism facilitating tumor development is unclear. Our earlier work suggested Ubc9 to play a critical role in BRCA1 loss mediated TNBC cell migration and metastasis. Collagen is one of the major components of the stromal extracellular matrix (ECM) network that influences tissue density. Its re-organization act as a scaffold aiding cancer cells to migrate causing metastasis. Ubc9 is known to increase the production of collagen, a key component of fibroglandular breast tissue, as well as tumorigenesis. Our work is based on the hypothesis that loss of BRCA1 in women with high breast density causes abnormal Ubc9 levels which upregulates collagen, fibronectin and inhibits SIRT1, β-catenin expression facilitating TNBC. We tested this hypothesis by studying the expression of total collagen, fibronectin, Ubc9, SIRT1, β-catenin in BRCA1 mutant TNBC cells and tumor sample derived from patient with dense breasts using immunofluorescence, immunohistochemistry, and collagen assay. Our results suggest for the first time that mutation or loss of BRCA1 function in women with fibrocystic breasts can lead to over expression of Ubc9, induction of collagen and; fibronectin, inhibition of SIRT1 and nuclear accumulation of β-catenin which could contribute to TNBC development. This network will aid not only in the identification of potential mechanism-based biomarkers that could detect disease early, but also enforce preventive measures that could reduce the risk for TNBC in women with high MD thus reducing the mortality associated with these cancers to achieve health equity.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
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