Abstract A073: TGF-beta receptor type-2 expression regulates breast cancer progression and is a prognostic marker for racial disparities

Abstract

Abstract Transforming growth factor β (TGFβ) is one of the most important signaling pathways associated with cellular proliferation, and its dysregulation can lead to tumor development. TGFβ can act as either a tumor suppressor or a tumor promoter depending upon the cellular context and genetic alterations. TGFβ receptor type-2 (TGFβR2) is the ligand-binding receptor, and data shows that the aberration of TGFβR2 is associated with many different cancers including colon, gastric, biliary, pulmonary, and ovarian cancers. In this study, we focused on uncovering the functional role of TGFβR2 in regulating breast cancer (BrCa) progression. First, we analyzed the genomic alterations of TGFβR2 in a sample set from The Cancer Genome Atlas (TCGA, n=1084) on the cBioprotal platform. We focused on obtaining genetic modifications, including mutations and copy number alteration. Data indicated that almost 25% of the patient’s samples having TGFβ amplified copy number; however, only less than one percent patients have amplified copy of TGFβR2 and other TGFβ receptors, within across this sample set. Next, we have screened the level of TGFβR2 protein expression in different BrCa cell-lines. We found that the elevated level of TGFβR2 is associated with the most aggressive triple-negative MDA-MB-231 cells. It is also found that the TGFβR2 is secreted into extracellular space. Therefore, we next evaluated the expression level of TGFβR2 in patient’s serum samples. We have well defined and categorized BrCa patients serum samples (n=240) from the Clinical Breast Care Project led by Walter Reed National Military Medical Center, Bethesda. The differential expression level of TGFβR2 in serum indicated that the elevated level of TGFβR2 is associated with BrCa patients compared with healthy individuals. Furthermore, the serum level of TGFβR2 is higher in the African American patient population when compared to Caucasian patients, and most significant differences were found within Luminal B1 sub-type BrCa cases. To better understand the mechanism of the higher level of TGFβR2 protein expression, in association with aggressiveness, we hypothesized that increased levels of TGFβ ligand are inducing the expression of the receptor (TGFβR2) and eventually stimulating the oncogenic pathway. We have used a series of BrCa cell lines and incubated them with different concentrations of TGFβ ligand. The level of TGFβR2 protein was increased in BrCa cell lines after TGFβ ligand treatment. Increased levels of TGFβ2 ligand induces the expression of the relevant receptor. In summary, we quantified the expression levels of TGFβR2 in patients’ serum samples, which can be used to create a set of stage and race-specific candidate protein biomarkers for BrCa. We also found that the increased level of TGFβ ligand-induced the expression of the TGFβR2 receptor. We can also conclude that TGFβR2 is an important biomarker and possibly plays a role in racial disparities in breast cancer progression. Citation Format: Alakesh Bera, John Karaian, Harvey B Pollard, Hai Hu, Craig D Shriver, Meera Srivastava. TGF-beta receptor type-2 expression regulates breast cancer progression and is a prognostic marker for racial disparities [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A073.