Cellular and molecular determinants of all-trans retinoic acid sensitivity in breast cancer: Luminal phenotype and RARα expression (original) (raw)
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Myoepithelial and luminal breast cancer cells exhibit different responses to all-trans retinoic acid
Cellular Oncology, 2015
Purpose Breast cancer is the leading cause of death among women worldwide. The exact role of luminal epithelial (LEP) and myoephitelial (MEP) cells in breast cancer development is as yet unclear, as also how retinoids may affect their behaviour. Here, we set out to evaluate whether retinoids may differentially regulate cell type-specific processes associated with breast cancer development using the bi-cellular LM38-LP murine mammary adenocarcinoma cell line as a model. Materials and methods The bi-cellular LM38-LP murine mammary cell line was used as a model throughout all experiments. LEP and MEP subpopulations were separated using inmunobeads, and the expression of genes known to be involved in epithelial to mysenchymal transition (EMT) was assessed by qPCR after all-trans retinoic acid (ATRA) treat-Keywords Mammary cancer. Retinoic acid receptors. Luminal and myoepithelial cells. EMT
Molecular and Cellular Endocrinology, 1995
Retinoic acid (RA) inhibits proliferation of estrogen receptor (ER)-positive human breast cancer cells, but not the growth of ERnegative cells. We have shown previously that ER-positive cells express higher levels of retinoic acid receptor (RAR) a, suggesting that RARtr gene expression may be regulated in breast cancer cells by estrogens. We here report that estradiol (E2) increases RARcz mRNA in a time-and concentration-dependent manner resulting in a marked increase in RARa protein expression, and present evidence that RARal is the only known isoform of RARo regulated by E2 in breast cancer cells. In parallel we demonstrate that ER-positive cells exhibit greater RA sensitivity in the presence of E2, suggesting that EZ-induced expression of RARal is involved in growth inhibition by RA. To directly investigate the role of RARcrl in RA-mediated growth inhibition, we introduced RARczl expression vectors into RA-resistant and ER-negative MDA-MB-231 cells. The RARal-transfected cells were growth inhibited by RA, while mock-and untransfected cells were unresponsive. Together, our data indicate that adequate levels of RARal, either generated by introduction of expression vectors or endogenously induced by estrogens, are required for growth inhibition of breast cancer cells by RA.
European Journal of Endocrinology, 1997
Retinoids seem to act as agents of chemoprevention and differentiation in breast diseases. Their action is mediated by nuclear receptors, retinoic acid receptors (RARa, RARb, RARg) and retinoid X receptors (RXRa, RXRb, RXRg) and modulated by cellular retinol binding proteins (CRBP). There are few published data on CRBP expression. In this study, we evaluated the expression of RARa, b and g and CRBP type I (CRBP-I) gene expression in fibrocystic disease (FD) and in breast cancer (BC), studying 14 FD and 20 BC surgical samples by reverse transcription (RT)-PCR. We also evaluated mRNA concentrations in cancer samples by a semiquantitative PCR method, co-amplifying RARa, RARb and CRBP-I genes with an unrelated gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), as internal control. All benign and malignant breast tissues expressed RARa, b and g, and CRBP-I mRNAs. A greater concentration of RARb mRNA was detected in cancer tissues with lower oestrogen and progesterone receptor concentrations, whereas RARa was detected in variable concentrations that were not related to those of steroid receptors. The CRBP-I concentration was similar in all samples studied. We demonstrated that all three RARs and CRBP-I transcripts are expressed in FD, and that RARb, RARg and CRBP-I mRNAs also are present in BC tissues. This indicates that both malignant and benign breast tissues may be target for retinoids, justifying the use of natural and synthetic vitamin A derivatives in the chemoprevention of breast disease.
Journal of Cellular Biochemistry, 1993
We and others have shown previously that retinoic acid (RA) selectively inhibits the growth of estrogen receptor (ER)–positive human breast carcinoma (HBC) cells and ER-negative cells are refractory to RA inhibition of growth. The ER-negative cells inherently express lower levels of RARα and retinoic acid response element (RARE)–mediated RA-induced CAT activity. In this study we report that when ER-negative MDA-MB-231 cells were transfected with the ER gene they not only expressed higher levels of RARα and RARE-mediated RA-induced CAT gene expression, but their growth was now inhibited by RA. Estrogen enhanced RARα gene expression not only in established ER-positive cell lines but also in ER-transfected MDA-MB-231 cells. The estrogen effect appears to be direct and at the gene transcription level since it did not alter the stability of RARα mRNA and cycloheximide failed to block estrogen-mediated enhancement of RARα gene expression. Our data strongly suggest that ER-mediated enhancement of RARα levels plays an important role in RA inhibition of HBC growth. In addition, we also report here that HBC cells appear to express a unique isoform(s) of RARα which was detected only when the full-length RARα cDNA was used as a probe; the RARα1 and RARα2 specific probes failed to hybridize with the HBC specific RARα message.
Anticancer research
Mechanisms by which the inhibitory effect of retinoic acid on tumor growth is attenuated as tumors progress to more advanced stages are unclear. This study utilizes a novel cell culture system of human breast epithelial cells (HBEC). Immortal (M13SV1), weakly tumorigenic (M13SV1-R2), and highly tumorigenic (M13SV1-R2N1) transformed Type I HBEC were derived sequentially from the same parental Type I HBEC (stem cells) developed from reduction mammoplasty of healthy women. Effects of all-trans retinoic acid (AT-RA) on the growth, protein expression of RAR-alpha, beta and gamma, and RARE transcriptional activation were determined. Results and AT-RA reduces proliferation rates of immortal and weakly tumorigenic cells, but not highly tumorigenic cells. This loss of response of highly tumorigenic cells to AT-RA is associated with overexpression of p185(c-erbB2/neu). It is not associated with decreased RAR-alpha, beta or gamma expression, or activation by AT-RA; RAR-alpha, beta and gamma ar...
Experimental Cell Research, 1997
tion [1, 2]. Recently, retinoids have also been found The expression of retinoic acid receptor-b (RARb) to be important for the prevention of certain cancers. mRNA is absent or down-regulated in a majority of Retinoids can halt the progression of disease in premabreast cancers, suggesting that loss of retinoic acid lignant lesions of the oral cavity, cervix, and skin, and receptor function may be a critical event in breast canthey are effective in preventing the development of seccer carcinogenesis. We developed an in vitro system to ond primary tumors of the aerodigestive tract and lung investigate whether the loss of retinoic acid receptor [3-13]. There is also evidence that retinoids are im-(RAR) function might affect the proliferation and portant for the chemoprevention of breast cancer. It structural differentiation of normal cultured human has been demonstrated that the risk of breast cancer mammary epithelial cells (HMECs). Utilizing a trunis increased for women with a lower dietary intake of cated retinoic acid receptor (RAR)-a construct exhibvitamin A and b-carotene but not for women with diiting dominant-negative activity against retinoic acid etary deficiencies of vitamins C or E [14]. Phase II trials receptor isoforms a, b, and g (DNRAR), we inhibited are under way to test the ability of fenretinide, a synnormal retinoic acid receptor function in HMECs. Supthetic retinoid, to prevent contralateral breast cancer pression of RAR function in HMECs resulted in re-[15, 16]. duced growth inhibition mediated by all-trans-reti-The association between vitamin A deficiency and noic acid (ATRA). Moreover, the doubling time of the development of cancer suggests that retinoid-de-HMECs expressing the DNRAR was significantly shortpendent signaling pathways have a role in the suppresened, associated with a decrease in the percentage of sion of carcinogenesis. Loss of expression of specific cells in G 1 and an increase in the percentage of cells nuclear retinoid receptors may abrogate these pathin S-phase relative to controls. In addition, HMECs exways. Therefore, in order to use retinoids in a clinically pressing the DNRAR cultured in prepared extracellurational manner it is important to define which receplar matrix exhibited a loss of extracellular matrix-intors are critical to the anticancer activity of retinoids. duced growth arrest and formation of a polarized ductal epthelium. Our results suggest that ATRA and The actions of retinoids are thought to be mediated RARs may play an important role in regulating the through specific nuclear retinoic acid receptors (RAR) 2 proliferation of HMECs and in promoting differentiaand retinoid X receptors (RXR) belonging to the steroid/ tion. ᭧ 1997 Academic Press thyroid superfamily of transcription factors [17-23]. Multiple retinoic acid receptors have been identified; among these are RARa, b, and g. RARa is expressed ubiquitously in adult tissue and RARg is primarily ex-2 Abbreviations used: RAR, retinoic acid receptor; RXR, retinoid X receptor; RA, retinoic acid; ATRA, all-trans-retinoic acid; HMEC, human mammary epithelial cells; RARb, retinoic acid receptor-b;
Retinoids and breast cancer: From basic studies to the clinic and back again
Cancer Treatment Reviews, 2014
All-trans retinoic acid (ATRA) is the most important active metabolite of vitamin A controlling segmentation in the developing organism and the homeostasis of various tissues in the adult. ATRA as well as natural and synthetic derivatives, collectively known as retinoids, are also promising agents in the treatment and chemoprevention of different types of neoplasia including breast cancer. The major aim of the present article is to review the basic knowledge acquired on the anti-tumor activity of classic retinoids, like ATRA, in mammary tumors, focusing on the underlying cellular and molecular mechanisms and the determinants of retinoid sensitivity/resistance. In the first part, an analysis of the large number of preclinical studies available is provided, stressing the point that this has resulted in a limited number of clinical trials. This is followed by an overview of the knowledge acquired on the role played by the retinoid nuclear receptors in the anti-tumor responses triggered by retinoids. The body of the article emphasizes the potential of ATRA and derivatives in modulating and in being influenced by some of the most relevant cellular pathways involved in the growth and progression of breast cancer. We review the studies centering on the cross-talk between retinoids and some of the growth-factor pathways which control the homeostasis of the mammary tumor cell. In addition, we consider the cross-talk with relevant intracellular second messenger pathways. The information provided lays the foundation for the development of rational and retinoid-based therapeutic strategies to be used for the management of breast cancer.
type I and retinoic acid receptors a2, 32, and y2 in human breast cancer cells
2000
Because the retinoic acid (RA) signal- ing pathway regulates cell proliferation and differen- tiation, inactivation of genes integral to the pathway represents a potential mechanism of carcinogenesis. We have studied in human breast cancer cells (T47D, MCF-7, ZR75-1, MDA-MB-231, and BT2O) the ex- pression of a subset of retinoid signaling genes that are themselves transcriptionally up-regulated by HA, the cellular