RESUMO
Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Carcinoma Basocelular/genética , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/genética , Transcriptoma , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Linhagem da Célula/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Cadeia alfa 1 do Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/virologia , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Vírus do Tumor Mamário do Camundongo/crescimento & desenvolvimento , Vírus do Tumor Mamário do Camundongo/patogenicidade , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Metástase Neoplásica , Gravidez , Análise de Célula Única , Microambiente Tumoral/genéticaRESUMO
Basal-like breast cancer (BLBC) is an aggressive molecular subtype that represents up to 15% of breast cancers. It occurs in younger patients, and typically shows rapid development of locoregional and distant metastasis, resulting in a relatively high mortality rate. Its defining features are that it is positive for basal cytokeratins and, epidermal growth factor receptor and/or c-Kit. Problematically, it is typically negative for the estrogen receptor and human epidermal growth factor receptor 2 (HER2), which means that it is unsuitable for either hormone therapy or targeted HER2 therapy. As a result, there are few therapeutic options for BLBC, and a major priority is to define molecular subgroups of BLBC that could be targeted therapeutically. In this review, we focus on the highly proliferative and anti-apoptotic phenotype of BLBC with the goal of defining potential therapeutic avenues, which could take advantage of these aspects of tumor development.
