Item Details

title

TGFBR1*6A AS A MODIFIER OF BREAST CANCER RISK AND PROGRESSION

author

Agyemang, Kojo

abstract

Less than 15% of hereditary/familial breast cancers can be explained by high and moderate penetrance autosomal-dominant genes such as BRCA1/2, TP53, ATM and PALB2. Recent studies suggest low penetrance genes can also explain heritable susceptibilities to breast cancer. The inclusion of low penetrance polymorphisms into genetic screening panels result in 40 to 50% increase in breast cancer risk detection among women, and 5 to 15% increase in detection among BRCA1/2-negative females. TGFBR1*6A is a low penetrance tumor susceptibility allele found in several cancer types. In breast cancer in particular, TGFBR1*6A is found in up to 12% of women and has been associated with breast cancer risk, odds ratio OR 1.15 (95% CI, 1.008 to 1.314). Functional studies show TGFBR1*6A increases growth, migration and invasion in stably transfected breast cancer cells. In this study, we investigate TGFBR1*6A association with breast cancer risk among MMTVneu knock-in mice. Breast tumor cells were isolated and examined for TGFBR1*6A influence on growth and clonogenicity. We found that TGFBR1*6A is associated with mouse mammary tumor formation, and tumor multiplicity. Tumor formation is highest among the homozygous TGFBR1*6A followed by the heterozygous TGFBR1*6A when compared to wild type TGFBR1 mice. Subsequent functional studies using isolated primary mouse breast tumor cells showed TGFBR1*6A increases growth and clonogenicity that can be associated cell cycle progression from G0/G1 phase. TGFBR1*6A regulates cell cycle progression by regulating mediator such as Cyclin D3, p21 and p27. Lower p27 expression was found to be crucial for TGFBR1*6A related growth. In relation to the tumor microenvironment, TGFBR1*6A is associated with breast tumor fibrosis. Our data showed higher fibrosis in human and mouse breast tumor tissues in a manner that is not related to fibronectin expression. Our data provides the background for future investigations into the molecular mediators of TGFBR1*6A tumorigenesis for biomarker and drug development for at-risk individuals.

subject

Breast cancer

Cell cycle

Cytoskeletal remodeling

Fibrosis

MMTVneu

TGFBR1*6A

contributor

Pasche, Boris (advisor)

Olivier, Michael (committee member)

Cook, Katherine (committee member)

Sun, Peiqing (committee member)

Singh, Ravi (committee member)

date

2023-07-25T17:48:27Z (accessioned)

2023 (issued)

degree

Cancer Biology (discipline)

embargo

2028-05-13 (terms)

2028-05-13 (liftdate)

identifier

http://hdl.handle.net/10339/102216 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation