Retinoids inhibit growth of breast cancer cell lines in culture and inhibit breast tumor growth in animals. Retinoid signals are mediated through the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), with each family represented by three distinct receptor genes designated alpha, beta, and gamma. All-trans retinoic acid (atRA) preferentially binds RARs but not RXRs; however, atRA can be converted intracellularly to 9-cis-retinoic acid (9-cis-RA), an RXR ligand. 9-cis-RA and 13-cis-RA bind both RARs and RXRs. Following stimulation by retinoids, RAR-RXR heterodimers and RXR-RXR homodimers can form. The receptor dimers bind to retinoic acid response elements or retinoid X response elements in the promoter sequences of target genes, and they modulate gene transcription. Effects of retinoids on signaling by ER and HERS have been reported. Inhibition of breast tumor cell growth by retinoids is greater for ER-positive cells than ER-negative cells, which may be partly related to alterations in retinoid metabolism. Some studies have found that RA increased the amount of ER in MCF7 breast cancer cells, although others reported that RA downregulated ER in this cell line. Regardless, activated RARs have been observed to exert anti-estrogenic effects by directly or indirectly impairing binding of ER to estrogen response elements (EREs). Conversely, the N-terminal region of ER-alpha modulates the transcriptional activity of RAR. Both RAR-alpha and RAR-beta have been implicated in the anti-proliferative effects of retinoids against breast cancer. RAR-alpha expression is correlated positively with ER and with RA sensitivity, and is inducible by estrogen. RAR-beta has been ascribed tumor suppressor=type activity and is often down regulated in breast cancer; it is inducible by atRA, and inducibility correlates with atRA sensitivity. In both ER-positive T47D cells and ER-negative SKBR3 cells, some evidence suggests that RAR-alpha is the receptor solely sufficient for the growth inhibition, cell cycle arrest, apoptosis, and modulation of RAR levels. Inhibition of breast cancer cell growth by atRA and 4-HPR has been associated with downregulation of HER2; while atRA induced morphologic changes consistent with differentiation, 4-HPR induced those of apoptosis. atRA and 9-cis-RA caused decreases in HER2 and HER3, and inhibited SKBR3 cell growth with cell cycle arrest and induction of apoptosis,, and the retinoids downregulated HER4 in T47D cells; atRA also downregulated HER2 and HER3 in MCF cells.Retinoids have been found to delay the onset of mammary tumors in HER2. Our lab wants to examine the effects of various retinoids (atRA, 9-cis-RA, and 13-cis-RA), tamoxifen, or combinations of these drugs on proliferation, cell cycle, differentiation, and apoptosis in BT474 and SKBR3 cells. Since retinoids and tamoxifen are individually agents that possess anti-tumor activity toward breast cancer, combinations of these drugs may translate into improved therapy for breast cancer

Combination of tamoxifen and retinoic acids, all trans, 9-cis, 13-cis, on spindle breast cancer cells: Monolayer films, spectral studies, and electron microscopy

247th National Meeting (2014)

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