How normal hormones in the breast sabotage chemotherapy

Why doesn't cisplatin work very well against breast cancer? The first response of most researchers would be to invoke something about genetic responses, but a pair of biologists from the University of Cincinnati have raised a quite different proposal this month in a review in Endocrine-Related Cancer: The unique hormonal milieu of the breast may contribute to chemoresistance.

In all of the intense collaboration to study chemotherapy sensitivity and resistance, it appears that this possibility has been overlooked, or perhaps just overshadowed by the intense focus on cancer genomics. For instance, a 2008 review in the British Journal of Cancer describing the "evolutionary arms race" to defeat chemotherapy resistance spoke at length about the promise of novel genomic approaches, without mentioning the possible influence of the hormonal environment. In their study of neoadjuvant cisplatin for triple-negative breast cancer, a team led by Judy Garber of Dana-Farber Cancer Institute assessed numerous factors including age and biomarkers such as p53 and BRCA1 as predictors of response. But she said they did not consider the effects of hormones on resistance.

Forget estrogen for a moment, which gets plenty of attention in breast cancer chemotherapy. Consider instead prolactin, a hormone uniquely designed to control mammary function. It's well known to increase proliferation of breast cancer cells and enhance their motility. And women with high blood levels of prolactin are known to have a poor prognosis for breast cancer. But its role in chemoresistance has been studied only briefly, and then apparently set aside. Prolactin was shown to counter the effects of chemotherapy in prostate and ovarian cancer and leukemia but not so much, oddly, in breast cancer.

Back in 2001, in vitro studies did show that co-treatment with a prolactin antagonist would potentiate the effect of cisplatin. Seven years later, another antagonist of prolactin was shown to enhance the effects of paclitaxel and doxorubicin on breast cancer cells in culture. But a mechanism for the effect of prolactin had not been proposed.

Now, mass spectroscopy studies by Elizabeth LaPensee and Nira Ben-Jonathan at the University of Cincinnati reveal that prolactin reduces DNA binding by cisplatin, in breast cancer cells, and therefore its ability to cause their death. Specifically, prolactin enhances the activity of the enzyme glutathione-S transferase, which binds with cisplatin and unhelpfully escorts it out of the cell.

Other factors may be at work. For instance, is estradiol also sabotaging breast cancer chemotherapy? For all the study of endogenous estrogens and their receptors in breast cancer, LaPensee and Ben-Jonathan observe, their possible effect on chemoresistance has also been overlooked-surprisingly, because besides enhancing cell growth, estrogen is known to reduce cell death. The team reports that the estrogen mimetic bisphenol A, present in many plastics, antagonizes cisplatin about as effectively as prolactin, although by a different mechanism. (Do plant-derived estrogens also have an effect?) Molecular cross-talk between estradiol and prolactin may complicate the picture, but this has not yet been studied.

While exciting, these possibilities remain speculative.

"I am afraid I don't think there is much data to support the [LaPensee' and Ben-Jonathan's] view," commented Garber when asked about it. "It is true that hormone receptor-positive breast cancer is not as sensitive to chemotherapy, but that does not speak to their point of view."