Abstract
Pericellular α3(V) collagen can affect the functioning of cells, such as adipocytes and pancreatic β cells. Here we show that α3(V) chains are an abundant product of normal mammary gland basal cells, and that α3(V) ablation in a mouse mammary tumour model inhibits mammary tumour progression by reducing the proliferative potential of tumour cells. These effects are shown to be primarily cell autonomous, from loss of α3(V) chains normally produced by tumour cells, in which they affect growth by enhancing the ability of cell surface proteoglycan glypican-1 to act as a co-receptor for FGF2. Thus, a mechanism is presented for microenvironmental influence on tumour growth. α3(V) chains are produced in both basal-like and luminal human breast tumours, and its expression levels are tightly coupled with those of glypican-1 across breast cancer types. Evidence indicates α3(V) chains as potential targets for inhibiting tumour growth and as markers of oncogenic transformation.
Highlights
Pericellular a3(V) collagen can affect the functioning of cells, such as adipocytes and pancreatic b cells
Tissues in which the a3(V) chain has been detected include white adipose tissue (WAT), skeletal muscle, and pancreatic islets, in which pericellular a3(V) chains are important to proper functioning of adipocytes, myofibres and pancreatic b cells, respectively6. a3(V) RNA is at relatively high levels in breast[7]
Effects of ablating the a3(V) gene Col5a3 on mammary tumour biology were studied in the MMTV-PyMT mouse model, which recapitulates many processes observed in human breast cancer progression and metastasis[10]
Summary
Pericellular a3(V) collagen can affect the functioning of cells, such as adipocytes and pancreatic b cells. The importance of collagenous ECM to breast carcinoma etiology, the specific upregulation of col(V) in desmoplasia, and the high a3(V) levels associated with mammary gland prompted us to assess possible a3(V) roles in mammary carcinoma aetiology Towards this end, effects of ablating the a3(V) gene Col5a3 on mammary tumour biology were studied in the MMTV-PyMT mouse model, which recapitulates many processes observed in human breast cancer progression and metastasis[10]. A3(V) chains and GPC1 are shown to be separately expressed by basal and luminal cells, respectively, in normal mouse and human mammary gland, but to be coexpressed in luminal and basal-like human breast tumours, which may provide a ‘gain of autonomy’ and growth advantage to tumour cells Such growth advantage may be of particular importance to luminal A tumours, with which high a3(V) and GPC1 expression levels are strongly associated. Data showing anti-a3(V) antibodies to slow tumour cell growth in vitro and in vivo suggest avenues for therapeutic interventions
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