Molecular features of luminal breast cancer defined through spatial and single‐cell transcriptomics

Abstract

BackgroundIntratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single‐cell RNA‐sequencing on patient‐derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor‐positive (ER+) breast cancer and to elucidate their importance in oestrogen‐dependent tumour growth.MethodsTwo PDXs of ‘ER‐high’ breast cancers with opposite oestrogen‐mediated growth responses were investigated: oestrogen‐suppressed GS3 (80–100% ER) and oestrogen‐dependent SC31 (40–90% ER) models. The observation was validated via single‐cell analyses on an ‘ER‐low’ PDX, GS1 (5% ER). The results from our spatial and single‐cell analyses were further supported by a public ER+ breast cancer single‐cell dataset and protein‐based dual immunohistochemistry (IHC) of SC31 examining important luminal cancer markers (i.e., ER, progesterone receptor and Ki67). The translational implication of our findings was assessed by clinical outcome analyses on publicly available cohorts.ResultsOur space‐gene‐function study revealed four spatially distinct compartments within ER+ breast cancers. These compartments showed functional diversity (oestrogen‐responsive, proliferative, hypoxia‐induced and inflammation‐related). The ‘proliferative’ population, rather than the ‘oestrogen‐responsive’ compartment, was crucial for oestrogen‐dependent tumour growth, leading to the acquisition of luminal B‐like features. The cells expressing typical oestrogen‐responsive genes like PGR were not directly linked to oestrogen‐dependent proliferation. Dual IHC analyses demonstrated the distinct contribution of the Ki67+ proliferative cells toward oestrogen‐mediated growth and their response to a CDK4/6 inhibitor. The gene signatures derived from the proliferative, hypoxia‐induced and inflammation‐related compartments were significantly correlated with worse clinical outcomes, while patients with the oestrogen‐responsive signature showed better prognoses, suggesting that this compartment would not be directly associated with oestrogen‐dependent tumour progression.ConclusionsOur study identified the gene signature in our ‘proliferative’ compartment as an important determinant of luminal cancer subtypes. This ‘proliferative’ cell population is a causative feature of luminal B breast cancer, contributing toward its aggressive behaviours.

DREAM On, DREAM Off: A Review of the Estrogen Paradox in Luminal A Breast Cancers

“…These include the cell lines used in the long-term estrogen deprivation studies. In addition, the only two estrogen-suppressed patient-derived xenograft models reported to date, WHIM16 [ 13 ] and GS3 [ 14 ], are both luminal B cell lines [ 15 , 16 ], suggesting that the apoptotic pathway triggered by estrogen has been elucidated exclusively in luminal B cells. The story might therefore be different in Luminal A cells.…”

Age-related Differences in Spatially Resolved Transcriptomic Profiles of Patients With Hormone Receptor-positive Breast Carcinoma

“…This high-plex spatially resolved RNA detection allows for transcriptomic characterization in spatially distinct areas. Some spatial transcriptomic studies have recently been reported in breast carcinoma (15)(16)(17)(18); however, only a few studies have analyzed the differences in gene expression between age groups of patients with HRpositive breast carcinoma. This study aimed to analyze the spatial transcriptomic profiles of younger and older patients with HR-positive breast carcinoma using DSP technology.…”