Analysis of gene expression patterns in triple negative breast cancer III: the retinoic acid receptor alpha and other TNBC candidate genes.

Triple negative breast cancer (TNBC) shares overlap with the basal or basal-like molecular subtype of breast cancer and is more frequently diagnosed in women of African descent (black women) for reasons not understood (1, 2). To understand genes whose expression may be of pertinence to the development or progression of triple negative breast cancer, we mined published microarray data (3) comparing global gene expression profiles of TNBC cases, identifying genes whose expression was least different among TNBC cases, indicating conservation of expression patterns suggestive of importance for TNBC biology. We identified the gene encoding the retinoic acid receptor alpha (RARA), a fatty acid elongase (ELOVL1), as well as multiple genes encoding molecules involved in epigenetic functions or with nucleic acid binding or modification properties, including TDRD7, KDM1B, PHF7, TAF5L, as well as the microRNA hsa-miR-605. Kaplan-Meier survival analysis revealed that expression levels of each of these genes correlated with survival outcomes in the basal subtype of human breast cancer, which shares significant overlap with triple negative breast cancer at the level of gene expression (2). RARA, ELOVL1, TDRD7, KDM1B, PHF7, TAF5L and hsa-miR-605 may be of relevance in understanding the etiology or progression of triple negative breast cancer. Together with our previous findings, the data allude to a potential pathogenic mechanism involving transcriptional perturbation of epigenetic machinery in triple negative breast cancer (4, 5).

Retinoic acid receptor alpha activation is necessary and sufficient for plasticity induced by recurrent central apnea

Reductions in respiratory-related synaptic inputs to inspiratory motor neurons initiate a form of plasticity that proportionally enhances inspiratory motor output, even in the absence of changing blood gases. This form of plasticity is known as inactivity-induced inspiratory motor facilitation (iMF). iMF triggered by brief, recurrent reductions in respiratory neural activity requires local retinoic acid (RA) synthesis, but receptor subtypes activated by RA are unknown. To test the hypothesis that retinoic acid receptor alpha (RARa) is necessary for iMF, RAR subtype-specific inhibitors were delivered intrathecally above the phrenic motor pool in urethane-anesthetized, ventilated rats prior to 5, ~1min central apneas (without hypoxia; separated by 5 min) while monitoring phrenic inspiratory output. Pre-treatment with a spinal RARa inhibitor impaired the capacity for recurrent central apnea to trigger long-lasting increases in phrenic inspiratory output, but plasticity was expressed in rats pre-treated with an RAR / inhibitor. Intrathecal RA application in the absence of reduced respiratory neural activity elicited an increase in phrenic inspiratory output, which was prevented by pre-treatment with an RARa inhibitor. These data indicate that spinal RARa activation is necessary for iMF triggered by recurrent reductions in respiratory neural activity, and that RARa activation in/near the phrenic motor pool in the absence of respiratory neural activity deprivation is sufficient to elicit phrenic inspiratory motor facilitation. Understanding cellular cascades underlying plasticity induced by reductions in respiratory neural activity may define avenues for pharmacological intervention in disorders in which endogenous compensatory mechanisms that defend on-going inspiratory motor output are impaired.

Trastuzumab treatment in human breast cancer is associated with over-expression of the retinoic acid receptor alpha (RARA).

Treatment with trastuzumab has been associated with an increased risk of central nervous system metastasis in patients with human breast cancer (1-5). We performed unbiased transcriptome profiling of primary tumors of patients treated with trastuzumab using published microarray and multiplexed gene expression datasets (6, 7) to understand the transcriptional makeup of breast tumors in the trastuzumab-treated patients. We found that the retinoid acid receptor alpha was among the genes most differentially expressed in the primary tumors of patients treated with trastuzumab; retinoid acid receptor alpha was expressed at significantly higher levels in tumors from patients with trastuzumab as compared to those not treated with trastuzumab. Increased retinoic acid receptor alpha expression is known to confer tamoxifen resistance to human breast cancers (8), and RARA expression is higher in tumors with higher proliferative capacity (9), suggesting that trastuzumab could contribute to resistance to endocrine therapy.

Retinoic acid receptor antagonists for male contraception: current status†

Retinoic acid receptor alpha (RARA), a nuclear receptor protein, has been validated as a target for male contraception by gene knockout studies and also pharmacologically using a pan-retinoic acid receptor antagonist. Retinoic acid receptor alpha activity is indispensable for the spermatogenic process, and therefore its antagonists have potential as male contraceptive agents. This review discusses the effects of systematic dosing regimen modifications of the orally bioavailable and reversible pan-antagonist BMS-189453 as well as studies with the alpha-selective antagonists BMS-189532 and BMS-189614 in a murine model. We also provide an overview of structure–activity studies of retinoic acid receptor alpha antagonists that provide insight for the design of novel alpha-selective ligands.