Chemoprevention of Hormone Receptor-Negative Breast Cancer: New Approaches Needed

Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230, USA.
Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2011; 188:147-62. DOI: 10.1007/978-3-642-10858-7_13
Source: PubMed


Results from clinical trials have demonstrated that it is possible to prevent estrogen-responsive breast cancers by targeting the estrogen receptor with selective estrogen receptor modulators (SERMs) (tamoxifen, raloxifene, or lasofoxifene) or with aromatase inhibitors (AIs) (anastrozole, letrozole, or exemestene). Results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective in preventing breast cancer than SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many ER-positive breast cancers, these drugs do not prevent ER-negative breast cancer. These results show that new approaches are needed for the prevention of this aggressive form of breast cancer. Our laboratory and clinical efforts have been focused on identifying critical molecular pathways in breast cells that can be targeted for the prevention of ER-negative breast cancer. Our preclinical studies have demonstrated that other nuclear receptors, such as RXR receptors, vitamin D receptors, as well as others are critical for the growth of ER-negative breast cells and for the transformation of these cells into ER-negative cancers. Other studies show that growth factor pathways including those activated by EGFR, Her2, and IGFR, which are activated in many ER-negative breast cancers, can be targeted for the prevention of ER-negative breast cancer in mice. Clinical studies have also shown that PARP inhibitors are effective for the treatment of breast cancers arising in BRCA-1 or -2 mutation carriers, suggesting that targeting PARP may also be useful for the prevention of breast cancers arising in these high-risk individuals. Most recently, we have demonstrated that ER-negative breast cancers can be subdivided into four distinct groups based on the kinases that they express. These groups include ER-negative/Her-2-positive groups (the MAPK and immunomodulatory groups) and ER-negative/Her2-negative groups (the S6K and the cell cycle checkpoint groups). These groups of ER-negative breast cancers can be targeted with kinase inhibitors specific for each subgroup. These preclinical studies have supported the development of several clinical trials testing targeted agents for the prevention of breast cancer. The results of a completed Phase II cancer prevention trial using the RXR ligand bexarotene in women at high risk of breast cancer will be reviewed, and the current status of an ongoing Phase II trial using the EGFR and Her2 kinase inhibitor lapatinib for the treatment of women with DCIS breast cancer will be presented. It is anticipated that in the future these molecularly targeted drugs will be combined with hormonal agents such as SERMs or aromatase inhibitors to prevent all forms of breast cancer.

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Available from: Ivan P Uray, Oct 05, 2015
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    • "Retinoids have been known and used for their inhibitory effects on breast cancer in chemoprevention and therapy. Moreover, selective estrogen receptor modulators (SERMs) (tamoxifen, raloxifene etc.) or aromatase inhibitors (AIs) (anastrozole, letrozole etc.) have been used successfully in chemoprevention of estrogen receptor positive (ER-positive) breast cancers [35]. But these drugs cannot prevent the progression of ER-negative breast cancer cases. "
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    ABSTRACT: In this study, novel (E)-3-(5-substituted-1H-indol-3-yl)-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (5(a-e)) derivatives were synthesized and their anticancer effects were determined in vitro. Novel indole retinoid compounds except 5e have anti-proliferative capacity in liver, breast and colon cancer cell lines. This anti-proliferative effect was further analyzed in breast cancer cell line panel by using the most potent compound 5a. It was determined that 5a can inhibit proliferation at very low IC(50) concentrations in all of the breast cancer cell lines. Here, we present some evidence on apoptotic termination of cancer cell proliferation which may be primarily driven by the inhibition of RXRα and, to a lesser extent, RXRγ.
    European Journal of Medicinal Chemistry 10/2012; 58C:346-354. DOI:10.1016/j.ejmech.2012.10.013 · 3.45 Impact Factor
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    • "The treatment of breast cancer patients has been revolutionized in part due to the use of diagnostic markers such as steroid receptors, Her2/neu and BRCA [1]. The clear demarcation of ER and PR positive, Her2/neu positive and triple negative (ER, PR, Her- 2/neu negative) patients has streamlined treatment approaches [2]. Generally Her2/neu positive patients have benefited from herceptin treatment whereas the steroid receptor positive patients receive anti-hormone therapy [3]. "
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    ABSTRACT: Aromatase inhibitors (AI) are considered as a first line therapy for ER+PR+ breast cancers. However, many patients acquire resistance to AI. In this study, we determined the response of antiprogestin CDB-4124 (Proellex) on the aromatase overexpressing and Letrozole resistant cell lines and also studies its mechanism of action in inhibition of breast cancer cell proliferation. For these studies we generated aromatase overexpressing T47D (T47Darom) and respective control (T47Dcon) breast cancer cell lines by stable transfection with plasmid containing CYP19A1 gene, or empty vector respectively. Letrozole resistant cell line (T47DaromLR) was generated by incubating T47Darom for 75 weeks in the presence of 10μM Letrozole. Cell proliferation was determined by MTT or crystal violet assays. Gene expressions were quantified by QRT-PCR whereas proteins were identified by western blot analyses, flow cytometry and immunofluorescence staining. Aromatase activity was determined by estradiol ELISA. The effects of Proellex on the anchorage independent growth were measured by soft agar colony formation. Statistical differences between the various groups were determined by Student's 't' test or ANOVA followed by Bonferroni's post hoc test. Results showed that T47Darom and T47DaromLR cell lines had significantly higher aromatase expression (mRNA; 80-90 fold and protein) and as a result exhibited increased aromatization of testosterone to estradiol as compared to T47Dcon. Both these cell lines showed enhanced growth in the presence of Testosterone (50-60%). In T47DaromLR cells increased PR-B and EGFR expression as compared to T47Dcon cells was observed. Proellex and other known aromatase inhibitors (Letrozole, Anastrozole, and Exemestane) inhibited testosterone induced cell proliferation and anchorage independent growth of T47Darom cells. Cell growth inhibition was significantly greater when cells were treated with Proellex alone or in combination with other AIs as compared to AIs alone. Proellex inhibited mRNA and protein levels of PR-B, reduced PRB/p300 complex formation in the nuclei and significantly reduced EGFR expression in T47Darom cells. Our results in the present study indicate that antiproliferative effect of Proellex is probably due to PR-B/EGFR modulation in ER+PR+, aromatase expressing cells. Overall these results suggest that antiprogestin, Proellex can be developed as a possible treatment strategy for aromatase overexpressing ER+/PR+ breast cancer patients as well as for aromatase inhibitor resistant breast cancer patients.
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    • "Statins may be useful for the prevention and treatment of cancer [1], [2], [3], [4]. Statins were first isolated as fungal metabolites that exhibited potent cholesterol lowering activity through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) [5]. "
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    ABSTRACT: 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins.
    PLoS ONE 12/2011; 6(12):e28813. DOI:10.1371/journal.pone.0028813 · 3.23 Impact Factor
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