YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is the most aggressive amongst all breast cancer (BC) subtypes. While TNBC tumors represent less than 20% of all BC subtypes, they are responsible for the most BC-related deaths. More significantly, when considering TNBC incidence across all racial/ethnic groups, TNBC accounts for less than 20% of all BCs. However, in non-Hispanic black women, the incidence rate of TNBC is more than 40%, which may be a contributing factor to the higher BC-related death rate in this population. These disparities remain strong even after accounting for differences in socioeconomic status, healthcare access, and lifestyle factors. Increased evidence now points to biological mechanisms that are intrinsic to the tumor that contribute to disparate TNBC disease burdens. Here, we show that YB1, a multifunction gene, plays a major role in the TNBC disparities between African American (AA) and Caucasian American (CA) women. We show in three independent TNBC tumors cohorts, that YB1 is significantly highly expressed in AA TNBC tumors when compared to CAs, and that increased levels of YB1 correlate with poor survival of AA patients with TNBC. We used a combination of genetic manipulation of YB1 and chemotherapy treatment, both in vitro and in animal models of TNBC to show that YB1 oncogenic activity is more enhanced in TNBC cell lines of AA origin, by increasing their tumorigenic and aggressive behaviors, trough the activation of cancer stem cell phenotype and resistance to chemotherapeutic treatments.

Disrupting the CmP signaling network unveils novel biomarkers for triple negative breast cancer in Caucasian American women

Objective: Triple-negative breast cancer (TNBC) constitutes ~15 percent of all diagnosed invasive breast cancer cases with limited options for treatment since immunotherapies that target the ER, PR and HER2 receptors are ineffective. Progesterone (PRG) is capable of inducing its effects through either classic, non-classic, or combined responses by binding to classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Under PRG-induced actions, we previously demonstrated that the CSC (CCM signaling complex) can couple both nPRs and mPRs into a CmPn signaling network which plays an important role in nPR(+) breast cancer tumorigeneses. We recently defined the novel CmP signaling network in TNBC cells, which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells. Materials and Methods: Under mPRs-specific steroid actions, we measured alterations to key tumorigenesis pathways in Caucasian American Women (CAW)-TNBC cells, with RNAseq and Proteomic approaches. Results: TNBC in CAW share similar altered signaling pathways, under mPRs-specific steroid actions, demonstrating the overall aggressive nature of TNBCs, regardless of racial differences. Furthermore, in this report, we have identified 21 new CAW-TNBC specific candidate biomarkers that reinforce the definitive role of the CmP signaling network in TNBC tumorigenesis, initially identified in our previous studies with AAW-TNBCs. This new set of potential prognostic biomarkers may revolutionize molecular mechanisms and currently known concepts of tumorigenesis in CAW-TNBCs, leading to hopeful new therapeutic strategies.

Causal inference multiple imputation investigation of the impact of cannabinoids and other substances on ethnic differentials in US testicular cancer incidence

Background Ethnic differences in testicular cancer rates (TCRs) are recognized internationally. Cannabis is a known risk factor for testicular cancer (TC) in multiple studies with dose-response effects demonstrated, however the interaction between ancestral and environmental mutagenic effects has not been characterized. We examined the effects of this presumed gene-environment interaction across US states. Methods State based TCR was downloaded from the Surveillance Epidemiology and End Results (SEER) website via SEERStat. Drug use data for cigarettes, alcohol use disorder, analgesics, cannabis and cocaine was taken from the National Survey of Drug Use and Health a nationally representative study conducted annually by the Substance Abuse and Mental Health Services Administration (SAMHSA) with a 74.1% response rate. Cannabinoid concentrations derived from Drug Enforcement Agency publications. Median household income and ethnicity data (Caucasian-American, African-American, Hispanic-American, Asian-American, American-Indian-Alaska-Native-American, Native-Hawaiian-Pacific-Islander-American) was from the US Census Bureau. Data were processed in R using instrumental regression, causal inference and multiple imputation. Results 1975–2017 TCR rose 41% in African-Americans and 78.1% in Caucasian-Americans; 2003–2017 TCR rose 36.1% in Hispanic-Americans and 102.9% in Asian-Pacific-Islander-Americans. Ethnicity-based scatterplot-time and boxplots for cannabis use and TCR closely mirrored each other. At inverse probability-weighted interactive robust regression including drugs, income and ethnicity, ethnic THC exposure was the most significant factor and was independently significant (β-estimate = 4.72 (2.04, 7.41), P = 0.0018). In a similar model THC, and cannabigerol were also significant (both β-estimate = 13.87 (6.33, 21.41), P = 0.0017). In additive instrumental models the interaction of ethnic THC exposure with Asian-American, Hispanic-American, and Native-Hawaiian-Pacific-Islander-American ethnicities was significant (β-estimate = − 0.63 (− 0.74, − 0.52), P = 3.6 × 10− 29, β-estimate = − 0.25 (− 0.32, − 0.18), P = 4.2 × 10− 13, β-estimate = − 0.19 (− 0.25, − 0.13), P = 3.4 × 10− 9). After multiple imputation, ethnic THC exposure became more significant (β-estimate = 0.68 (0.62, 0.74), P = 1.80 × 10− 92). 25/33 e-Values > 1.25 ranging up to 1.07 × 105. Liberalization of cannabis laws was linked with higher TCR’s in Caucasian-Americans (β-estimate = 0.09 (0.06, 0.12), P = 6.5 × 10− 10) and African-Americans (β-estimate = 0.22 (0.12, 0.32), P = 4.4 × 10− 5) and when dichotomized to illegal v. others (t = 6.195, P = 1.18 × 10− 9 and t = 4.50, P = 3.33 × 10− 5). Conclusion Cannabis is shown to be a TC risk factor for all ethnicities including Caucasian-American and African-American ancestries, albeit at different rates. For both ancestries cannabis legalization elevated TCR. Dose-response and causal relationships are demonstrated.

Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer

Late diagnosis, unreliable prognostic assessment, and poorly-guided therapeutic planning result in dismal survival of ovarian cancer (OC) patients. Therefore, identifying novel functional biomarker(s) is highly desired for improved clinical management. MYB is an oncogenic transcription factor with emerging functional significance in OC. Here we examined its clinicopathologic significance by immunohistochemistry and TCGA/GTex data analyses. Aberrant MYB expression was detected in 94% of OC cases (n = 373), but not in the normal ovarian tissues (n = 23). MYB was overexpressed in all major epithelial OC histological subtypes exhibiting the highest incidence (~ 97%) and overall expression in serous and mucinous carcinomas. MYB expression correlated positively with tumor grades and stages. Moreover, MYB exhibited race-specific prognostic association. Moderate-to-high MYB levels were significantly associated with both poor overall- (p = 0.02) and progression-free (p = 0.02) survival in African American (AA), but not in the Caucasian American (CA) patients. Consistent with immunohistochemistry data, we observed significantly higher MYB transcripts in OC cases (n = 426) than normal ovary (n = 88). MYB transcripts were significantly higher in all epithelial OC subtypes, compared to normal, and its greater levels predicted poor survival in AA OC, but not CA OC, patients. Thus, MYB appears to be a useful clinical biomarker for prognostication, especially in AA patients.

Computational features of TIL architecture are differentially prognostic of uterine cancer between African and Caucasian American women.

5585 Background: Although the vast majority of endometrial cancer (EC) is early-stage and thus, curable by surgery, chemotherapy, and radiotherapy (with at least 85% 5-year OS), a fraction of them are aggressive neoplasms such as high-grade or deeply invasive lesions and thus exhibit poor prognosis. African American (AA) women are disproportionately affected by high-grade EC and have 80% higher mortality rate compared with Caucasian American (CA) women. In this work, we evaluated the prognostic ability of computational measurements of architecture of tumor-infiltrating lymphocytes (ArcTIL) from H&E slide images for EC. We also investigated the presence of morphologic differences in terms of ArcTIL features between AA and CA women and whether ArcTIL based population-specific models were more prognostic of OS in AA women compared to a population-agnostic model. Methods: The study included digitized H&E tissue slides from 445 post-surgery EC patients from TCGA, with further chemotherapy, or radiotherapy, including only the AA and CA patients, patients without reported race or from other populations were excluded. The dataset was divided into discovery (D1, n = 300), and a validation set (D2, n = 145), while ensuring population balance between two splits (D1(AA) = 65, D1(CA) = 235, D2(AA) = 37, D2(CA) = 108). A machine learning approach was employed to identify tumor regions, and tumor-associated stroma on the diagnostic slides and then used to automatically identify TILs within these compartments. Graph network theory based computational algorithms were used to capture 85 quantitative descriptors of the architectural patterns of intratumoral and stromal TILs. A multivariable Cox regression model (MCRM) was used to create population specific-prognostic models (MAA, MCA) and a population-agnostic model (MAA+CA)) to predict OS. All 3 models were evaluated on D2(AA), D2(CA), and D2. Results: MAA identified 4 prognostic features relating to interaction of TIL clusters with cancer nuclei in stromal compartment and was prognostic of OS on D2(AA) (see Table) but not prognostic in D2(CA) nor D2(AA+CA). MCA and MAA+CA identified respectively 7 and 6 prognostic features relating to interaction of TIL clusters with cancer nuclei (both in the epithelial and stromal regions) and were prognostic of OS on D2(CA) and D2, but not prognostic in D2(AA). Conclusions: Our findings suggest an important role of stromal TIL architecture in prognosticating OS in AA women with EC, while epithelial TIL features were more prognostic in CA women. These findings need to be validated in larger, multi-site validation sets.[Table: see text]

Racially Disparate Expression of mTOR/ERK-1/2 Allied Proteins in Cancer

Recent studies revealed that ethnic differences in mechanistic target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK-1/2) signaling pathways might be associated with the development and progression of different human malignancies. The African American (AA) population has an increased rate of cancer incidence and mortality compared to the Caucasian American (CA) population. Although the socioeconomic differences across different ethnic groups contribute to the disparity in developing different cancers, recent scientific evidence indicates the association of molecular and genetic variations in racial disparities of different human malignancies. The mTOR and ERK-1/2 signaling pathways are one of the well-known oncogenic signaling mechanisms that regulate diverse molecular and phenotypic aspects of normal as well as cancer cells in response to different external or internal stimuli. To date, very few studies have been carried out to explore the significance of racial disparity with abnormal mTOR and ERK-1/2 kinase signaling pathways, which may contribute to the development of aggressive human cancers. In this review, we discuss the differential regulation of mTOR and ERK-1/2 kinase signaling pathways across different ethnic groups, especially between AA and CA populations. Notably, we observed that key signaling proteins associated with mTOR and ERK-1/2 pathway including transforming growth factor-beta (TGF-β), Akt, and VEGFR showed racially disparate expression in cancer patients. Overall, this review article encompasses the significance of racially disparate signaling molecules related to mTOR/ERK1/2 and their potential in developing tailor-made anti-cancer therapies.

Mastering Diversity and Gaining a Competitive Advantage on University Campuses

The purpose of this chapter is to examine the salient classroom and university interactions between students and instructors of different cultural backgrounds and to offer insight as to how educators and other leaders on campus might maximize effectiveness with diverse groups, gaining a competitive advantage. Inspired by the lived experiences of an African-American graduate student in a department staffed predominately of Caucasian-American faculty members, this chapter calls instructors and other leaders at educational institutions to cultivate healthy professional relationships with students and to create environments conducive to learning by employing pedagogical strategies which acknowledge the unique learning styles of learners.