Lineage plasticity enables low-ER luminal tumors to evolve and gain basal-like traits

• Published in: Breast cancer research : BCR 2023-03, Vol.25 (1), p.23-23, Article 23
• Main Authors: Mohamed, Gadisti Aisha, Mahmood, Sundis, Ognjenovic, Nevena B, Lee, Min Kyung, Wilkins, Owen M, Christensen, Brock C, Muller, Kristen E, Pattabiraman, Diwakar R
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Biomarkers; Breast cancer; Cancer; Cancer therapies; Chemotherapy; Decision making; Development and progression; Disease Models, Animal; Endocrine therapy; Epithelial cells; Estrogen; Estrogen receptors; Gene Expression; Health aspects; Keratin; Lineage plasticity; Low-ER; Lumino-basal heterogeneity; Mammary gland; Mammary Neoplasms, Animal; Metastasis; Mice; MMTV-PyMT; Phenotype; Phenotypes; Plasticity; Prognosis; Receptors, Estrogen; RNA sequencing; Single-cell RNA sequencing; Sox10 protein; Tumor cells; Tumors
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-023-01621-8

Stratifying breast cancer into specific molecular or histologic subtypes aids in therapeutic decision-making and predicting outcomes; however, these subtypes may not be as distinct as previously thought. Patients with luminal-like, estrogen receptor (ER)-expressing tumors have better prognosis than patients with more aggressive, triple-negative or basal-like tumors. There is, however, a subset of luminal-like tumors that express lower levels of ER, which exhibit more basal-like features. We have found that breast tumors expressing lower levels of ER, traditionally considered to be luminal-like, represent a distinct subset of breast cancer characterized by the emergence of basal-like features. Lineage tracing of low-ER tumors in the MMTV-PyMT mouse mammary tumor model revealed that basal marker-expressing cells arose from normal luminal epithelial cells, suggesting that luminal-to-basal plasticity is responsible for the evolution and emergence of basal-like characteristics. This plasticity allows tumor cells to gain a new lumino-basal phenotype, thus leading to intratumoral lumino-basal heterogeneity. Single-cell RNA sequencing revealed SOX10 as a potential driver for this plasticity, which is known among breast tumors to be almost exclusively expressed in triple-negative breast cancer (TNBC) and was also found to be highly expressed in low-ER tumors. These findings suggest that basal-like tumors may result from the evolutionary progression of luminal tumors with low ER expression.