New Understanding of Mechanisms Revealed in Development of Breast Cancer and Resistance to Treatment

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Greater insights into the etiology of breast cancer can lead to more effective treatments.
Greater insights into the etiology of breast cancer can lead to more effective treatments.

Researchers identified an enzyme, called LATS, which plays a role in the development and treatment of breast cancer in a molecular and mouse study. LATS cooperates with other proteins in these processes. These findings were presented in a study published in the journal Nature.1

Researchers wanted to address why breast cancer develops and why some patients are resistant to treatment. In approximately 70% of all breast cancers, the tumor has estrogen receptors. These tumors can usually be treated with drugs that disrupt estrogen signaling at the receptor and result in tumor degeneration.

Nearly one-third of tumors, however, do not respond to these treatments or become refractory. Understanding the etiology of breast cancer and the development of resistance to treatment could facilitate the development of new drugs.

A high-content confocal image-based short hairpin RNA screen in breast cell lines revealed the tumor suppressor LATS, particularly LATS1 and LATS2, as involved in regulating breast cell fate. Once LATS was ablated, the number of luminal precursor cells increased. Luminal precursor cells are the source of most kinds of breast cancers in humans.

LATS joins the estrogen receptor alpha with protein degradation machinery in normal breast tissue. Without LATS, proper degradation of the receptor can no longer occur. Lack of degradation of the receptor can result in resistance to therapy.

In this research, cancer cells without LATS were resistant to fluvestrant, an estrogen-receptor antagonist that promotes its degradation. In addition, the delection of LATS stabilized the proteins YPA and TAZ. These proteins are both increased in many different types of cancer and increase cell proliferation.

Reference

1. Britschgi A, Duss S, Kim S, et al. The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with Erα. Nature. 2017 Jan 9. doi: 10.1038/nature20829. [Epub ahead of print]

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