Molecular BIology of Cancer Topics
Drug Resistance and Hormonal Dependance
Some cancers are itrinsically resistant to chemotherapy: lung, colon, kidney, liver, pancreaas. These cancers are major causes of cancer deaths. Other cancers initially respond to chemotherapy, but become refractory/resistant, i.e. aquire drug resistance. Drug resistance is the primary cause of cancer chemotherapy failure.
Drug resistance is due to genetic changes in the tumor (gene amplification, point mutation ?), for example amplification of dihydrofolate reductase leads to resistance to methotrexate.
So drug resistance is mediated by transport proteins like P-glycoprotein, am ATP-dependent transmembrane pump found on the plasma membrane of cells that line tubules or ducts in the kidney, lung, liver and colon. P-glycoprotein may play a general role in excretion of substances from cells. Elevation of P-glycoprotein levels leads to resistance to many chemotherapeutic agents by decreasiong drug uptake and retention by the tumor cell. Competitive substrates for P-glycoprotein, e.g verapamil, modulate drug resistance.
The gene coding for P-glycoprotein is known as mdr1 (multidrug resistance). Drug-resistant human tumors have elecated mdr1. Transfection of mdr1 confers the drug-resistance phenotype.
p53 causes G1 growth arrest in most cells and apoptosis in some cells (thymocytes) in response to DNA damage. p53 positive tumor cells are more responsive to radiation or chemotherapeutic treatment. An it seems like the inhability of p53-negative cells to uncergo apoptosis confers them resistance to chemotherapy with many different drugs. Transfection of wild-type p53 into p53-negative cells restore their sensibility to chemotherapeutic drugs. Experimentally, apoptosis in response to some chemotherapeutic drugs occur only in the presence of wild-type p53. p53 induces apoptosis by actin as a transcription factor of the human Bax gene.
Antiangiogenic
therapy of experimental cancers does not induce acquired drug resistance (Boeh
et. al. 1997; Nature 390:27). Successive cycles of therapy using anti-tumor
agents leads to acquired drug resistance as a result of selection of drug-resistant
tumor cels. In contrast, repeated treatment with an angiogenesis inhibitor
such as endostatin does not induce resistance in its target cells (endothelial
vascular cells). By attacking the endothelial cells of the new blood vessels
being formed to nourish the grwing tumor, angiogenesis inhibitors destroy
the source of nutrients to the tumor, which regressess and may becoe dormant.
Several cancer types are progressed by sex hormones. 20% of prostate cancers are responsive to dihydrotestosterone. 40% of female cancers are responsive to estrogen or progesterone: breat, ovarian, endometrial.
Breast cancer is the leading cancer in U.S. women (1 in 8 women), second only to lung cancer in causing death. Patients with localized breast cancer usually suvive more than 5 years after treatment (96% survival). 78% of patients with regional disease (lymph nodes) and 21% with metastatic disease survive 5 years after treatment. The main risk factors for breast cancer are (1) having a first degree relative (mother, sister) with breast cancer, and (2) high total lifetime exposure to "unopposed" estrogen. Less than 10% of breast cancers are inherited, due to BECA1 or BRCA2 gene mutations.
The concept of unopposed estrogens refers to the blocking effect of progesterone on estrogen receptor production. This usually hapens naturally during pregnancy, when both estrogen and progesterone are present in high quantities. Events that would increase the lifetime exposure to unopposed estrogen are an early menarche, later age at first pregnancy and late menopause.
The estrogen receptor belongs to the family of nuclear steroid receptors. Activated ER forms homodimers that bind the Estrogen Response Element (ERE) in the promoter region of genes controlled by estrogen.
Estrogens have many effects in tissues. They stimulate growth in breast and endometrium, and increases bone density. In the cardiovascular system, it lowers serum cholesterol. At puberty, estrogen enhances growth of reproductive organs, genitalia and breasts. During pregnancy it increases proliferation of mammary gland tissue and ducts.
Breast cancer arrises from breast ductal epithelial cells. Mammary tumor growth is dependent on estrogen. Tumor growth is greately reduced by ovarectomy, and is restored by exogenous estrogen. Anti estrogens lilke tamoxifen have antitumor activity. Tamoxifen binds to the estyrogen receptor and have antiestrogenic effects in the breast, while having estrogenic effects in the endometrium (probably due to different transcriptional coactivators expressed in each tissue). Antiestrogens such as tamoxifen may be useful in the treatment and prevention of human breast cancer. Since ER+ and progesterone receptor positive (PR+) tumors are the most responsive to hormonal therapy, human breast cancers are tested for the presense of these receptors in order to determine if antiestrogen therapy is appropriate.