In a study of premenopausal breast cancer patients, a protein known as Pak1 (p21-activated kinase 1) appeared to interfere with the effectiveness of tamoxifen. These results were published in the Journal of the National Cancer Institute.
Each year breast cancer is diagnosed in over 200,000 women in the U.S. alone. Many of these breast cancers will be hormone receptor-positive, meaning that they are stimulated to grow by the circulating female hormones estrogen and/or progesterone.
Historically, the most common hormonal treatment for estrogen receptor-positive breast cancer was an antiestrogen called tamoxifen (Nolvadex®). Tamoxifen blocks estrogen receptors and prevents the estrogen-stimulated growth of breast cancer cells. There are now newer agents that help to prevent estrogen/progesterone from stimulating cancer cell growth.
Pak1 is a protein that plays a role in the normal function of cells. Because Pak1 can activate a specific type of estrogen receptor, breast tumors with high levels of Pak1 may be less responsive to tamoxifen.
To evaluate the effect of Pak1 on tamoxifen response, researchers conducted a study among 403 premenopausal women with stage II breast cancer.
The patients had been randomly assigned to receive or not to receive two years of adjuvant treatment with tamoxifen. The effect of tamoxifen on survival without a cancer recurrence was assessed separately for women with low and high Pak1 levels. Levels of Pak1 were measured in tumor cells and were classified on a scale of 0 (low) to 5 (high). The presence or absence of Pak1 in the nuclei of tumor cells was also assessed.
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Of the 403 breast tumors evaluated, 327 had a Pak1 level on the low end of the scale (score of 0, 1, or 2) and 76 had a Pak1 level on the high end of the scale (score of 3, 4, or 5). Pak1 was found in the nuclei of tumor cells in 24 of the 403 tumors.
- Among women with estrogen receptor-positive breast cancer and low levels of Pak1 (score of 0,1, or 2), treatment with tamoxifen resulted in a lower risk of breast cancer recurrence.
- Among women with high levels of Pak1 (score of 3, 4, or 5) treatment with tamoxifen did not influence risk of breast cancer recurrence.
- The presence or absence of Pak1 in the nucleus appeared to be even more strongly linked with tamoxifen response. Women with evidence of Pak1 in the nuclei of tumor cells were significantly less likely to respond to tamoxifen than women without evidence of Pak1 in the nuclei of tumor cells.
The researchers conclude that these findings support a role for Pak1 in estrogen receptor signaling and tamoxifen resistance. Although this finding will need to be confirmed by additional studies, the researchers note that their results “raise the possibility that premenopausal breast cancer patients whose tumors overexpress Pak1 most likely will not respond to tamoxifen and may need to be offered alternative endocrine treatment.”
Reference: Holm C, Rayala S, Jirström K et al. Association Between Pak1 Expression and Subcellular Localization and Tamoxifen Resistance in Breast Cancer Patients. Journal of the National Cancer Institute. 2006;98:671-80.
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