Canonical WNT/β- catenin signaling plays pivotal roles in mammary development and tumorigenesis; and aberrant activation of this pathway is frequently observed in human breast cancer, correlating with poor outcome. However, the mechanisms underlying WNT-mediated mammary tumorigenesis remain incompletely understood. Here, we used mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice, which develop aggressive mammary adenomas, to examine whether Limb-Bud-and-Heart (LBH) - a WNT/β-catenin target transcription co-factor overexpressed in human triple-negative breast cancers with WNT pathway hyperactivation, contributes to WNT-induced tumorigenesis. We found LBH is specifically overexpressed in basal epithelial tumor cells of MMTV-WNT1 mammary tumors reminiscent of its’ basal cell-restricted expression pattern in the normal postnatal mammary gland. To determine the role of LBH in mammary tumorigenesis, we crossed MMTV-Wnt1 mice with epithelial-specific Keratin 14/K14-Cre;LbhloxP knockout mice. Mammary glands from virgin LBH-deficient MMTV-Wnt1 mice exhibited reduced hyperplasia, cell proliferation and increased apoptosis. Importantly, LBH inactivation in mammary epithelium significantly delayed tumor onset in MMTV-Wnt1 transgenic mice, with a median tumor-free survival of 32.5 weeks compared to 22.5 weeks in control LBH wild type MMTV-Wnt1 mice (p<0.05). This data provides the first evidence that LBH plays an essential role in WNT-induced mammary tumorigenesis by promoting hyperplastic growth and tumor formation.

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Despite significant progress in the early detection, treatment, and survivorship of cancer in recent decades, cancer disparities continue to plague segments of the US population. Many of these cancer disparities, especially those among historically marginalized racial and ethnic groups and those with lower socioeconomic resources, are caused and perpetuated by social and structural barriers to health.These social and structural barriers, which operate beyond the framework of cancer control, also systematically increase vulnerability to and decrease adaptive capacity for the deleterious effects of anthropogenic climate change. The established and emerging overlap between climate vulnerability and cancer risk presents complex challenges to cancer control, specifically among populations who suffer compounding hazards and intersectional vulnerabilities. By embracing these intersections, we may be able to conceptualize promising new research frameworks and programmatic opportunities that decrease vulnerability to a wide range of climate and health threats to advance health equity. K E Y W O R D S cancer, cancer disparities, climate change, environmental indicators, social determinants of health, social vulnerability DISPARITIES IN CLIMATE VULNERABILITY AND CANCER RISKCancer is the second leading cause of death in the United States.Overall, the cancer death rate has fallen 32% from its peak in 1991 to 2019, the most recent year for which data are available. Yet there are well-documented differences in who survives cancer, which are preceded by differences in who gets screened for cancer, receives a timely cancer diagnosis, and receives access to quality cancer care.So, even as we see improvements in cancer survival rates, survival is still less frequent for Black people for almost every cancer type relative to their White counterparts. 1 It has become increasingly evident that these differences, termed cancer disparities, result in part from socially driven inequities that render historically marginalized populations (i.e., ethnic, racial, and sexual minorities, women, and those of lower socioeconomic status) in our society disproportionately vulnerable to chronic disease. [2][3][4][5] The key feature of socially driven inequities is that instead of being intrinsic to individuals or populations, they are extrinsic and driven by structural and systemic systems that dictate and maintain power, privilege, and oppression.

Cancer stem cells (CSCs) initiate tumors, resist treatment, and seed lethal metastases; yet CSC-specific treatments are lacking. Aggressive, treatment-resistant triple-negative breast cancers (TNBC) exhibit WNT pathway activation and are CSC enriched. Here, we show that Limb-Bud- and-Heart (LBH), a WNT/β-catenin target required for normal mammary stem cell self-renewal, marks poor prognosis, stem-like TNBC, and is a key controller of breast cancer stemness. LBH is specifically expressed in tumor-initiating CD44+CD24-/low breast CSCs. LBH overexpression confers stem-like, metastatic traits on both TNBC and luminal origin, non-TNBC breast cancer cells by activating stem cell transcriptional programs. Importantly, silencing LBH potently suppresses tumor initiation and metastasis in vivo, and sensitizes TNBC cells to chemotherapy. LBH knockout in the MMTV-Wnt1 breast cancer mouse model, furthermore, revealed LBH is required for WNT-driven breast CSC expansion. Our findings identify LBH as an essential CSC driver downstream of WNT, and a new molecular target for anti-cancer stem cell therapy.

Purpose: Social and structural contributors to social vulnerability have been associated with cancer disparities across the continuum. This study aimed to explore relationships between indicators of neighborhood social vulnerability and participation in breast, cervical and colorectal cancer screening in Miami-Dade County. Methods: Data were obtained at the census tract level from the United States Census Bureau American Community Survey (2014-2018), the Centers for Disease Control and Prevention (CDC) Social Vulnerability Index (2018), and the CDC PLACES dataset (2018). This analysis was restricted to Miami-Dade census tracts for which PLACES data was available on mammography (n=135), cervical cancer screening (n=115), and colorectal screening (n=136) participation. Census tracts were stratified into tertiles based on screening participation, then social vulnerability indicators were assessed among the tertiles. Principal component analysis (PCA) was used to identify characteristics responsible for most variability in breast, cervical and colorectal cancer screening. Results: Mammography participation was 51.76%, 58.80%, and 65.65% in the lower, middle, and upper tertiles, respectively. Among these tracts, per capita income (p&lt;.001), earning an income below poverty (p&lt;.001), educational attainment below earning an HS diploma (p&lt;.001), the proportion of non-Hispanic White residents (p&lt;.001), unemployed residents (p&lt;.001), residents with a disability (p&lt;.001), and people with no computer or limited access to the internet (p&lt;.001) were significantly different between the tertiles. Cervical cancer screening participation was 79.60%, 84.36%, and 87.80% in the lower, middle, and upper tertiles, respectively. Among these tracts, per capita income (p&lt;.001), earning an income below poverty (p&lt;.001), educational attainment below earning an HS diploma (p&lt;.001), and proportion of single-parent households with children under age 17 (p&lt;.001), non-Hispanic White residents (p&lt;.001), unemployed residents (p&lt;.001), residents with a disability (p&lt;.001), and people with no computer or limited access to the internet (p&lt;.001) were significantly different between the screening tertiles. Colorectal cancer screening participation was 79.26%, 81.06%, and 85.26% in the lower, middle, and upper tertiles, respectively. Among these tracts, per capita income (p&lt;.01), earning an income below poverty (p&lt;.004), educational attainment below earning an HS diploma (p&lt;.001), the proportion of residents with a disability (p&lt;.001), and people with no computer or limited access to the internet (p&lt;.001) were significantly different between the screening tertiles. Conclusions: These data suggest that social vulnerability is associated with cancer screening uptake, namely mammography, cervical cancer screening, and colorectal cancer screening. Further investigation of the social and structural factors contributing to disparities in cancer screening will help appropriately allocate resources and craft effective interventions to reduce the burden of cancer among those most vulnerable. Citation Format: Kilan C. Ashad-Bishop, Jordan A. Baeker-Bispo, Zinzi D. Bailey, Erin K. Kobetz. Exploring relationships between neighborhood social vulnerability and cancer screening in Miami-Dade County [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C083.

Limb-Bud and Heart (LBH) is a developmental transcription co-factor deregulated in cancer, with reported oncogenic and tumor suppressive effects. However, LBH expression in most cancer types remains unknown, impeding understanding of its mechanistic function Here, we performed systematic bioinformatic and TMA analysis for LBH in >20 different cancer types. LBH was overexpressed in most cancers compared to normal tissues (>1.5-fold; p < 0.05), including colon-rectal, pancreatic, esophageal, liver, stomach, bladder, kidney, prostate, testicular, brain, head & neck cancers, and sarcoma, correlating with poor prognosis. The cancer types showing LBH downregulation were lung, melanoma, ovarian, cervical, and uterine cancer, while both LBH over- and under-expression were observed in hematopoietic malignancies. In cancers with LBH overexpression, the LBH locus was frequently hypomethylated, identifying DNA hypomethylation as a potential mechanism for LBH dysregulation. Pathway analysis identified a universal, prognostically significant correlation between LBH overexpression and the WNT-Integrin signaling pathways. Validation of the clinical association of LBH with WNT activation in gastrointestinal cancer cell lines, and in colorectal patient samples by IHC uncovered that LBH is specifically expressed in tumor cells with nuclear beta-catenin at the invasive front. Collectively, these data reveal a high degree of LBH dysregulation in cancer and establish LBH as pan-cancer biomarker for detecting WNT hyperactivation in clinical specimens.

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There is increasing evidence that basal-like triple negative breast cancer (TNBC) originates from luminal mammary epithelial cells. Specific gene signatures have already been experimentally proven to serve as genetic lineage switches that, when overexpressed, transform pre-malignant luminal cells to oncogenic cells with basal, stem-like characteristics. Conversely, depletion of these genes in oncogenic cells with basal, stem-like characteristics leads to luminal differentiation. These studies suggest that during the earliest steps of neoplastic transformation, specific gene sets can alter cell fate decisions and differentiation status in mammary epithelial cells, which ultimately contributes to the heterogeneity of breast tumors. Our lab has identified a novel Wnt/β-Catenin target gene, Limb bud and heart (LBH) that is majorly overexpressed in TNBC. LBH is a regulator of the basal mammary stem cell lineage and repressor of luminal differentiation via induction of ΔNp63 and repression of estrogen receptor alpha. LBH is required for the self-renewal and maintenance of adult basal mammary stem cells, which tend to be enriched in TNBC. Knockout studies in mice have shown that genetic ablation of LBH does not impair embryogenesis or normal adult organ function, making it a possible therapeutic target. Using crosses between MMTV-Wnt-1 transgenic mice and K14Cre LBHloxP knockout mice, we are studying the effect of LBH ablation in the basal cells of the mammary epithelium downstream of ectopic Wnt expression in the mammary gland. We postulated that LBH may be an effector of Wnt-driven TNBC, therefore its inhibition would lead to decreased Wnt-induced mammary gland hyperplasia and tumor formation. In our model, LBH ablation in the basal mammary epithelium of female Wnt transgenic mice reduces mammary gland hyperplasia and delays tumor onset. MMTV-Wnt-1 driven, LBH-null tumors also exhibit histopathological differences indicative of a luminal to basal conversion. There is an urgent need to elucidate mechanisms underlying TNBC development and progression and find reliable avenues for treatment. Our data indicates a role for Lbh as a novel effector for Wnt-driven TNBC and further studies may prove antagonism of Lbh to be a novel method to control TNBC progression. Citation Format: Kilan C. Ashad-Bishop, Karoline Briegel. Loss of the stem cell and basal lineage regulator LBH delays onset of basal-like triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2876. doi:10.1158/1538-7445.AM2017-2876