Open AccessCellular and molecular determinants of all‐ trans retinoic acid sensitivity in breast cancer: Luminal phenotype and RAR α expression
Author(s) -
Centritto Floriana,
Paroni Gabriela,
Bolis Marco,
Garattini Silvio Ken,
Kurosaki Mami,
Barzago Maria Monica,
Zanetti Adriana,
Fisher James Neil,
Scott Mark Francis,
Pattini Linda,
Lupi Monica,
Ubezio Paolo,
Piccotti Francesca,
Zambelli Alberto,
Rizzo Paola,
Gianni' Maurizio,
Fratelli Maddalena,
Terao Mineko,
Garattini Enrico
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404670
Subject(s) - retinoic acid , phenotype , breast cancer , cancer research , biology , cancer , medicine , genetics , gene
Forty‐two cell lines recapitulating mammary carcinoma heterogeneity were profiled for all‐ trans retinoic acid ( ATRA ) sensitivity. Luminal and ER + (estrogen‐receptor‐positive) cell lines are generally sensitive to ATRA , while refractoriness/low sensitivity is associated with a Basal phenotype and HER 2 positivity. Indeed, only 2 Basal cell lines ( MDA ‐ MB 157 and HCC ‐1599 ) are highly sensitive to the retinoid. Sensitivity of HCC ‐1599 cells is confirmed in xenotransplanted mice. Short‐term tissue‐slice cultures of surgical samples validate the cell‐line results and support the concept that a high proportion of Luminal/ ER + carcinomas are ATRA sensitive, while triple‐negative ( Basal ) and HER 2‐positive tumors tend to be retinoid resistant. Pathway‐oriented analysis of the constitutive gene‐expression profiles in the cell lines identifies RAR α as the member of the retinoid pathway directly associated with a Luminal phenotype, estrogen positivity and ATRA sensitivity. RAR α3 is the major transcript in ATRA ‐sensitive cells and tumors. Studies in selected cell lines with agonists/antagonists confirm that RAR α is the principal mediator of ATRA responsiveness. RAR α over‐expression sensitizes retinoid‐resistant MDA ‐ MB 453 cells to ATRA anti‐proliferative action. Conversely, silencing of RAR α in retinoid‐sensitive SKBR 3 cells abrogates ATRA responsiveness. All this is paralleled by similar effects on ATRA ‐dependent inhibition of cell motility, indicating that RAR α may mediate also ATRA anti‐metastatic effects. We define gene sets of predictive potential which are associated with ATRA sensitivity in breast cancer cell lines and validate them in short‐term tissue cultures of Luminal/ ER + and triple‐negative tumors. In these last models, we determine the perturbations in the transcriptomic profiles afforded by ATRA . The study provides fundamental information for the development of retinoid‐based therapeutic strategies aimed at the stratified treatment of breast cancer subtypes.