Biology subjects

Oropeza, E.

Publications and source records attributed to Oropeza, E..

3 recordsLinked to original sources

bioRxiv2025

The impact of patient biology on racial disparities in breast cancer outcome

Hormone receptor positive (HR+) breast cancer is the most common subtype of breast cancer diagnosed globally. Despite effective targeted therapies, HR+ breast cancer remains a leading cause of cancer-related death in women. Long-standing epidemiological research identifies significantly worse outcomes for Black women diagnosed with HR+ breast cancer relative to White women. While structural factors such as access to healthcare and education level contribute to this outcome disparity, it persists even in analyses where these factors are controlled. In-depth analyses of the somatic molecular biology that may underlie these outcome disparities are hampered by a lack of datasets that represent Black patient populations. Here, we generate a HR+ breast cancer patient transcriptomic dataset that overrepresents Black women and controls for access to healthcare and education level. We find that signatures relating to the tumor microenvironment, i.e. collagen deposition and prognostically unfavorable T-cell landscapes are enriched in HR+ tumors from Black women. Importantly, we find, using experimental model systems in vitro and in vivo, that race-aligned collagen deposition patterns are at least partially attributable to tumor cell-intrinsic signaling and critical for Black breast cancer metastasis. We also find that unfavorable T-cell signatures in HR+ tumors from Black women, which have previously been attributed to race and ancestry, are more strongly poverty-aligned. Using multiple independent datasets, we identify STAT4 as a potential master regulator of this poverty-associated tumor immune signature. Together, these findings provide new evidence that somatic molecular biology of breast cancer patients can be modified by multiple structural factors such as self-identified race and poverty burden to promote poor patient outcomes. Integrating an understanding of structural factors into molecular cancer research is critical for implementing truly personalized, and maximally effective, oncology systems.

cancer biology↗

bioRxiv2024

Aberrant subcellular localization of mismatch repair protein MLH1 dysregulates the cell cycle to create new therapeutic opportunities

Estrogen receptor positive (ER+) breast cancer is one of the most common causes of cancer-related death in women. Mortality is largely driven by recurrence of treatment-resistant disease after many years of apparent response, making the molecular events that cause recurrence a critical area of investigation. Loss of expression of MLH1, a tumor suppressor best studied in its role in mismatch repair, induces resistance of ER+ breast cancer cells to standard estrogen-targeting therapies. It does so by delinking cell cycle progression from estrogen regulation, a role distinct from its function in mismatch repair. MLH1 loss, as currently clinically diagnosed by detecting genomic instability or by immunohistochemistry for absence of protein, occurs in 12-15% of all cancers. Here, we demonstrate that sub-clonal, patient-derived mutations in MLH1, which neither impact protein abundance nor contribute sufficiently to genomic instability to be detected diagnostically, seed endocrine treatment resistance by enabling estrogen-independent growth in vitro, ex vivo in patient-derived organoids (p=0.005) and in vivo (p=0.0001). The mechanism underlying this endocrine treatment resistance is aberrant localization of MLH1 to the cytoplasm in vitro and in vivo (p=0.04), which precludes cell cycle arrest in response to endocrine therapy while simultaneously rendering cells acutely dependent on CDK4/6 activity. Consequently, administration of CDK4/6 inhibitors causes extreme regression in cells with cytoplasmic MLH1 compared to control cell populations with nuclear localization of MLH1 in vitro (p=0.00000009), ex vivo (p=0.01) and in vivo (p=0.01). As aberrant cytoplasmic localization occurs in an additional [~]12% of ER+ breast cancer patients, it constitutes a new, major contributor to MLH1 dysregulation. The potential applicability of cytoplasmic MLH1 as a predictor of responsiveness to existing targeted therapies in a hard-to-treat breast cancer subtype posits an update of current clinical diagnostic criteria and therapeutic strategies. This is particularly important in the adjuvant setting where identification of biomarkers predicting responsiveness to CDK4/6 inhibitors remains an urgent, unmet clinical need.

cancer biology↗

bioRxiv2020

Cell-free DNA as a biomarker for prostate cancer: elevated concentration and decreased fragment size

PurposeProstate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. Materials and MethodsThis study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. ResultsPlasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR5 ng/mL = 1.34, P = 0.027) or to being a control (OR5 ng/mL = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR5bp = 0.77, P = 0.0008). ConclusionThis study suggests that cfDNA concentration and average cfDNA fragment size may provide a quick, cost-effective approach to help determine which patients will benefit most from further screening and/or disease monitoring to help improve prostate cancer outcomes.

cancer biology↗