Abstract
Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype. In our study, we demonstrate that alpha(v)beta(3) integrin (Int-αvβ3), previously shown to play a role in cancer progression, promoted differentiation and growth arrest of organoids derived from luminal A breast cancer cells grown in their relevant three-dimensional microenvironment. These organoids differentiated into normal-like acini resembling a benign stage of breast tissue. Likewise, we demonstrate that Int-αvβ3 is selectively expressed in the epithelium of the benign stage of breast tissues, and is lost during the early stages of luminal A breast cancer progression. Notably, the organoids' reversion into normal-like acini was mediated by cancer luminal progenitor-like cells expressing both EpCAMhighCD49flowCD24+ and Int-αvβ3. Furthermore, downregulation of Notch4 expression and downstream signaling was shown to mediate Int-αvβ3-induced reversion. Intriguingly, when luminal A breast cancer cells expressing Int-αvβ3 were injected into a humanized mouse model, differentiated tumors developed when compared with that generated by control cells. Hence, our data suggest that promoting differentiation of luminal A breast cancer cells by signaling emanating from Int-αvβ3 can potentially promote ‘normalization' of their malignant phenotype and may prevent the malignant cells from progressing.
Highlights
Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype
We demonstrate that alpha(v)beta(3) integrin (Int-αvβ3), previously shown to play a role in cancer progression, promoted differentiation and growth arrest of organoids derived from luminal A breast cancer cells grown in their relevant three-dimensional microenvironment
We demonstrate that Int-αvβ[3] is selectively expressed in the epithelium of the benign stage of breast tissues, and is lost during the early stages of luminal A breast cancer progression
Summary
Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype. Its contribution to breast cancer progression has been un-conclusive given conflicting results in the literature concerning the outcome of inhibiting Int-αvβ[3] expression/ activity on breast tumor cells.[5,6] Recently, low concentrations of RGD-mimetic Int-αvβ[3] and integrin-αvβ[5] (Int-αvβ5) inhibitors were shown to paradoxically stimulate tumor growth and angiogenesis.[5,7,8] regulation of tumor progression by tumor and stromal β3 integrin (Int-β3) were shown to vary in breast cancer models.[9] Here we demonstrate that Int-αvβ[3] is selectively expressed in the epithelium of the benign stage of breast tissues and is lost during early stages of luminal A (positive for estrogen and progesterone receptors) breast cancer progression These surprising results suggest that Int-β3 expression might maintain the differentiated state of premalignant tissue via its engagement with its restrictive normal microenvironment, the latter acting as a gatekeeper during neoplastic progression.[10] we hypothesized that Int-β3 re-expression in luminal A breast cancer cells will promote their differentiation in conjunction with their microenvironment. Tumors developed by MCF-7-Intβ[3] cell were highly differentiated compared with MCF-7 tumors, grown in an in vivo humanized mouse model.[13,14] All together, these findings demonstrate for the first time to our knowledge that CLPs, which are present in luminal A breast cancer cell lines and tissues,[15] can be induced to differentiate into acinar-like organoids via expression of Int-αvβ[3] in the 3D system and in vivo to a more differentiated phenotype
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