Biology subjects

Curtin, M. C.

Publications and source records attributed to Curtin, M. C..

3 recordsLinked to original sources

bioRxiv2025

Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis

Obesity is predicted to become the largest modifiable risk factor for breast cancer in postmenopausal women, yet the mechanisms underlying this association are unclear. We identified a novel role for the endogenous oxylipin 9S-HODE, secreted by lean adipocytes, to induce ferroptosis in breast cancer cells while sparing normal breast epithelial cells. Obese adipocytes fail to secrete 9S-HODE, suggesting that the loss of ferroptosis induction significantly contributes to the acceleration of obesity-associated breast cancer. Consequently, the inhibition of ferroptosis accelerates breast cancer in lean, but not obese, mice. Further, 9S-HODE inhibits the growth of patient-derived breast cancer organoids, and supplementing 9S-HODE into tumors in obese mice is sufficient to reduce tumor burden, underscoring its potential as a therapeutic agent.

cancer biology↗

bioRxiv2025

Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology. While obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 orthotopic model of obesity-accelerated BC growth in immune-competent mice, we investigated the direct role of systemic lipids in tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in obese individuals.

cancer biology↗

bioRxiv2024

Zinc Alpha-2-Glycoprotein (ZAG/AZGP1) secreted by triple-negative breast cancer promotes tumor microenvironment fibrosis.

Obesity is a predisposition factor for breast cancer, suggesting a localized, reciprocal interaction between breast cancer cells and the surrounding mammary white adipose tissue. To investigate how breast cancer cells alter the composition and function of adipose tissue, we screened the secretomes of ten human breast cancer cell lines for the ability to modulate the differentiation of adipocyte stem and progenitor cells (ASPC). The screen identified a key adipogenic modulator, Zinc Alpha-2-Glycoprotein (ZAG/AZGP1), secreted by triple-negative breast cancer (TNBC) cells. TNBC-secreted ZAG inhibits adipogenesis and instead induces the expression of fibrotic genes. Accordingly, depletion of ZAG in TNBC cells attenuates fibrosis in white adipose tissue and inhibits tumor growth. Further, high expression of ZAG in TNBC patients, but not other clinical subtypes of breast cancer, is linked to poor prognosis. Our findings suggest a role of TNBC-secreted ZAG in promoting the transdifferentiation of ASPCs into cancer-associated fibroblasts to support tumorigenesis.

cancer biology↗