Elsevier

The Breast

Volume 14, Issue 6, December 2005, Pages 458-465
The Breast

ORIGINAL ARTICLE
Endocrine responsiveness: Understanding how progesterone receptor can be used to select endocrine therapy

https://doi.org/10.1016/j.breast.2005.08.024Get rights and content

Summary

The receptor for the female hormone progesterone (PR), like that for estrogen (ER), is an important predictive marker for response to endocrine therapy in patients with breast cancer. PR exists as two isoforms, A and B. PR is important in mammary gland development and excess production of PRB is associated with breast cancer risk. Overabundance of PRA is related to resistance to tamoxifen. Total loss of PR is linked to reduced benefit from tamoxifen in both the adjuvant and metastatic settings. The predictive significance of PR expression was originally explained on the basis that PR is an ER-regulated gene and its presence indicates a functioning ER pathway and, therefore, an endocrine-responsive tumor. More recent data, however, suggest an alternative explanation. While many studies show that loss of PR predicts relative resistance to the antiestrogen tamoxifen, a recent study suggests that PR loss may not indicate resistance to aromatase inhibition. The finding that PR loss may not correlate with resistance to aromatase inhibition may be related to crosstalk between ER and PR and growth factor receptor pathways such as HER2. PR loss in some tumors is due to excessive growth factor receptor signaling (overexpression of HER2), which downregulates expression of the PR gene. Neoadjuvant studies also show that HER2 signaling is associated with tamoxifen resistance, but not resistance to aromatase inhibitors. Therefore, high HER2 signaling could explain both PR loss and resistance to tamoxifen while the response to aromatase inhibitors is maintained. In this way, PR loss in some tumors may be a surrogate marker for increased signaling through the growth factor receptor tyrosine kinase pathway and it may help clinicians decide between initial use of an aromatase inhibitor or tamoxifen in the individual patient.

Section snippets

Estrogen receptors in breast cancer

The importance of steroid hormones in breast cancer pathogenesis and progression has been known for decades and the roles of the cognate receptors for estrogen (ER) and progesterone (PR) as important predictive markers have been confirmed by numerous studies. Estrogen and its receptor are crucial for breast cancer development and they are successful targets for prevention and treatment.1, 2, 3, 4 All endocrine therapies for breast cancer target ER in one way or another. PR is important in the

Progesterone receptor and response to tamoxifen

Studies performed 25 years ago confirmed the value of ER as an important biomarker that predicted response to different kinds of endocrine therapy. When PR was identified as an ER-regulated gene, it was hypothesized as described earlier that ER+/PR+ tumors would be more responsive to endocrine therapy than ER+/PR− tumors. Retrospective studies of patients with metastatic disease, most receiving tamoxifen, supported this idea (Table 1).31 PR− tumors consistently respond less well to endocrine

Membrane-initiated ER signaling

In addition to the function of ER as a transcriptional regulator in the nucleus, growing evidence suggests that a small pool of ER is located outside the nucleus in the cytoplasm or in the plasma membrane. The binding of estrogen to this receptor activates signals that appear within minutes and are, therefore, too rapid to be explained by a transcriptional mechanism.49 This membrane ER can modulate activities through several signaling pathways normally thought to be regulated by growth factors

Clinical implications

If the biology suggested by these laboratory studies is mirrored in breast tumors in patients, then it might be expected that ER+ tumors overexpressing HER2 would have reduced PR levels compared with those tumors not overexpressing HER2. Several clinical reports do suggest that high GF receptor content is associated with loss of PR.27, 69, 71, 72 Looking at this question from the opposite perspective, ER+ tumors lacking PR might be expected to express high levels of GF receptors such as IGF-1

Acknowledgments

This work was supported in part by a breast cancer SPORE Grant (P50 CA 50183), and a Komen Foundation Postdoctoral Fellowship (PDF0403061).

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