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HDLG5 IS IDENTIFIED AS A PRIMARY TARGET OF PROGESTINS IN MCF-7 CELLS

  1. Top of page
  2. HDLG5 IS IDENTIFIED AS A PRIMARY TARGET OF PROGESTINS IN MCF-7 CELLS
  3. EAT YOUR VEGGIES
  4. UPRT, DIRECTED BY RESTRICTED REPLICATION-COMPETENT ADENOVIRUS, INCREASES PANCREATIC CANCER CELLS' SENSITIVITY TO 5-FU
  5. PROBLEMS WITH MAMMOGRAPHY

Progesterone can have opposing effects on the growth of both normal and malignant breast epithelial cells; it initially stimulates entry from G1 into S-phase, but prolonged exposure can cause growth inhibition. Moreover, progestins can inhibit the estrogen-stimulated growth that is often associated with increased differentiation of these cells. In order to begin to identify some of the effectors used by progesterone, Purmonen et al. utilized differential display-PCR to find genes whose expression is directly regulated by the activation of the progesterone receptor in cultured breast cancer cells. On pages 1–6, they report their finding that the expression of hDlg5 is directly upregulated by treatment with the synthetic progestin medroxyprogesterone acetate (MPA) in MCF-7, T47D and ZR-75-1 cells.

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Figure 1. Time-depenent hDlg5mRNA regulation by MPA in MCF-7 cells

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hDlg5 is the fifth human homolog of the Drosophila gene dlg [lethal (l) discs-large], which was initially identified as a tumor suppressor. It is a member of the growing family of MAGUKs – membrane-associated guanylate kinase homologs – and the first family member reported to be hormonally regulated. Like other MAGUKs, KIAA0583 (the hDL5 protein) contains an SH3 domain and a characteristic GUK domain, so named for its homology to the yeast guanylate kinase. It also has five PDZ domains, two more than are typical, and a PEST sequence, suggesting that it may have a short half-life.

This finding supports the idea that MAGUKs may have tumor suppressor activity; and as a primary target of progestins, hDlg5 may play an important role in regulating the growth and differentiation of breast cancer cells.

EAT YOUR VEGGIES

  1. Top of page
  2. HDLG5 IS IDENTIFIED AS A PRIMARY TARGET OF PROGESTINS IN MCF-7 CELLS
  3. EAT YOUR VEGGIES
  4. UPRT, DIRECTED BY RESTRICTED REPLICATION-COMPETENT ADENOVIRUS, INCREASES PANCREATIC CANCER CELLS' SENSITIVITY TO 5-FU
  5. PROBLEMS WITH MAMMOGRAPHY

We have all always known that fruits and vegetables are good for us. Now, to all of the benefits that a diet rich in fresh produce confers, we can add protection from gastric cancer.

In order to examine the potential association between consumption of fruits and vegetables and the risk of gastric cancer, Kobayashi et al. performed a population-based prospective study in four public health center areas in Japan. Participants were followed for 10 years, and adjustments were made during data analysis for age, gender, and location. In their paper on pages 39–44 Kobayashi et al. report that people who reported eating fruits and vegetables had a lower risk of gastric cancer than those who did not. Interestingly, the risk did not decline in a stepwise manner. Pickled vegetables and fruit and vegetable juices were not taken into account.

These findings agree with those from previous prospective and case-control studies. However, these are more reliable because fruit and vegetable consumption was assessed before any gastric cancer could be diagnosed, whereas in the earlier studies reports of fruit and vegetable consumption were susceptible to a potentially biased or mistaken recall of past dieting habits.

UPRT, DIRECTED BY RESTRICTED REPLICATION-COMPETENT ADENOVIRUS, INCREASES PANCREATIC CANCER CELLS' SENSITIVITY TO 5-FU

  1. Top of page
  2. HDLG5 IS IDENTIFIED AS A PRIMARY TARGET OF PROGESTINS IN MCF-7 CELLS
  3. EAT YOUR VEGGIES
  4. UPRT, DIRECTED BY RESTRICTED REPLICATION-COMPETENT ADENOVIRUS, INCREASES PANCREATIC CANCER CELLS' SENSITIVITY TO 5-FU
  5. PROBLEMS WITH MAMMOGRAPHY

Pancreatic cancer is the fifth leading cause of cancer death in the United States. It has been treated with 5-fluorouracil (5-FU), but drug resistance has been a crucial therapeutic problem. On pages 51–59, Oonuma et al. demonstrate that they can combat 5-FU resistance with E. coli uracil phosphoribosiltransferase (UPRT).

5-FU exerts its cytotoxic activity partially by inhibiting thymidylate synthase (TS); it does this by forming a ternary complex that is synthesized by TS, 5,10-methylenetetrahydrofolate, and fluorodeoxyuridine monophosphate (F-dUMP). UPRT catalyzes the synthesis of fluorouridine monophosphate, a precursor of F-dUMP; it thus enhances 5-FU's inhibition of TS and improves the sensitivity of pancreatic cancer cells to 5-FU. Oonuma et al. transduce UPRT specifically into tumor cells using restricted replication-competent adenovirus that lack the 55kDa E1B protein.

Tumors are reduced dramatically. And because the modified adenovirus can replicate only in cells lacking a functional p53 protein—such as approximately 50% of pancreatic cancer cells—normal cells are not transduced. This means that the patients (mice with xenotransplanted human pancreatic tumors) are spared the adverse gastrointestinal effects often associated with chemotherapy.

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Figure 2. Therapeutic effect of UPRT-expressing restricted replication competent adenoviral vectors and 5-FU in vivo

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PROBLEMS WITH MAMMOGRAPHY

  1. Top of page
  2. HDLG5 IS IDENTIFIED AS A PRIMARY TARGET OF PROGESTINS IN MCF-7 CELLS
  3. EAT YOUR VEGGIES
  4. UPRT, DIRECTED BY RESTRICTED REPLICATION-COMPETENT ADENOVIRUS, INCREASES PANCREATIC CANCER CELLS' SENSITIVITY TO 5-FU
  5. PROBLEMS WITH MAMMOGRAPHY

Although mammograms should aid in detecting and treating breast cancers, they sometimes tend to confuse a diagnosis rather than clarify it, as is too often the case with informative technologies. Three concurrent reports deal with different facets of this timely issue.

On pages 86–90, Karamouzis et al. evaluate the correlation between mammographically detected malignant-appearing microcalcifications and the expression of molecular markers involved in proliferation and apoptosis in nonpalpable breast carcinomas. Because the pathobiologic profile of nonpalpable breast carcinomas cannot be determined accurately based solely on the mammographic appearance of microcalcifications, the identification of new markers associated with disease progression and tumor aggressiveness is imperative. They found statistically significant associations between malignant-appearing microcalcifications and nuclear localization of the estrogen receptor, and with expression of the progesterone receptor, HER-2/neu, Bax, Fas, and DFF. The latter three proteins are pro-apoptotic molecules.

In their report on pages 29–33, Maskarinec et al. note that the absolute size of the dense areas in a mammogram appears to be a better measure of breast cancer risk than the relative density, especially when comparing ethnic groups with distinct physical properties such as breast size. They reached this conclusion by comparing the mammograms from Japanese women in Japan with those of Japanese and Caucasian women in Hawaii. The incidence of breast cancer in each population—lowest in Japanese women in Japan, intermediate in Japanese women in Hawaii and highest in the Caucasian women—is reflected best by the size of the dense areas in their respective mammograms.

Lastly, on pages 91–95, Tilanus-Linthorst et al. report their disturbing finding that BRCA1/2 mutations contribute to false negatives in mammograms. This is probably due to the specific histologic phenotype of BRCA1/2-associated breast cancers; particularly the fact that they exhibit prominent pushing margins around the tumor. This contributes to a mammographic image of a smooth mass, rather than the more typically malignant spiculated mass. High breast density can also contribute to falsely negative mammograms. The authors suggest that in BRCA1/2 mutation carriers, any mass in a mammogram should be regarded, and treated, with suspicion.